Hexahydrooxazinopterine compounds

ABSTRACT

The present invention provides mTOR inhibitors of the formula 
     
       
         
         
             
             
         
       
     
     wherein the variables are as defined herein. Also provided are pharmaceutical compositions, kits and articles of manufacture comprising such compounds; methods of making the compounds and intermediates thereof; and methods of using the compounds.

RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Nos.61/238,064, filed Aug. 28, 2009 and 61/313,608, filed Mar. 12, 2010,which are incorporated herein by reference.

FIELD OF THE INVENTION

The present invention relates to medicinal chemistry and pharmaceuticalscience. Provided herein are compounds that inhibit mammalian target ofrapamycin (mTOR).

BACKGROUND OF THE INVENTION

mTOR is a serine/threonine kinase and has been identified as a regulatorof protein synthesis as well as cell growth and proliferation. Also,mTOR has been shown to regulate the response of tumor cells to nutrientsand growth factors as well as the ability of tumors to promoteangiogenesis. Thus, inhibitors of mTOR activity are being activelystudied as potential anti-proliferative agents. Currently inhibitors ofmTOR are approved for immunosuppression and cancer treatment.

Inhibition of mTOR function by small molecules results in a loss oftransmission of upstream activating signals (i.e., from growth factorreceptors) to downstream effectors of cell growth. Rapamycin, aninhibitor of mTOR, inhibits proliferation or growth of cells derivedfrom a range of tissue types such as smooth muscle and T-cells as wellas cells derived from a diverse range of tumor types includingrhabdomyosarcoma, neuroblastoma, glioblastoma and medulloblastoma, smallcell lung cancer, osteosarcoma, pancreatic carcinoma and breast andprostate carcinoma. Moreover, rapamycin and its derivatives have shownthe ability to potentiate the cytotoxicity of a number of common cancerchemotherapies including cisplatin, camptothecin and doxorubicin.

It has been shown that mTOR functions in two distinct complexes (mTORC1and mTORC2). Rapamycin primarily inhibits the mTORC1 complex whilelargely sparing mTORC2 activity. Thus, one strategy is to identifycompounds that are capable of inhibiting mTORC1 and mTORC2 mediatedactivity in the cell. The compounds of the present invention are suchinhibitors of mTOR and are useful to treat disorders associated withmTOR.

In addition, mTOR Complex1-S6K1 integratesvarious extrinsic signals thatregulate cell growth and metabolism. Experiments with rapamycin provideda link between mTOR Complex1-S6K1 and adipogenesis. Also it has beendemonstrated that S6K1-deficient mice are protected from diet and ageinduced obesity.

Certain inhibitors of PI3K are disclosed in WO2006/005915. Certaininhibitors of mTOR and/or PI3K are disclosed in WO 2008/023180.

SUMMARY OF THE INVENTION

The present invention provides compounds of formula I:

G₁ is selected from the group consisting of N and CR₇;G₂ is selected from the group consisting of C═O and CH₂;Ar is selected from the group consisting of C₄₋₁₄ aryl and C₁₋₁₀heteroaryl;m is 0, 1, 2, 3, or 4;R₁ is, each time taken, independently selected from the group consistingof halo, cyano, optionally substituted C₁₋₆ alkyl, C₁₋₈ sulfonyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₁₋₄ alkoxy, C₀₋₈ alkylamino, optionallysubstituted C₄₋₁₄ aryl, optionally substituted C₄₋₁₄ aryloxy, optionallysubstituted C₁₋₁₀ heteroaryloxy, C₁₋₅ oxycarbonyl, C₁₋₅ carbonyloxy,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₆heterocycloalkyl, optionally substituted C₁₋₁₀ heteroaryl, hydroxy,nitro, —C(O)NR₈R₉, —NHC(O)NR₈R₉, —NHC(O)OR₁₀, —NH(SO₂)NHR₈,—NHC(O)NHNR₈R₉, —NHC(S)NR₈R₉, —NHC(═NR₁₁)NR₈R₉, —NHC(SR₁₂)NR₈R₉, and—NHC(═NR₁₁)OR₁₃;R₂ is selected from the group consisting of hydrogen, halo, cyano,optionally substituted C₁₋₆ alkyl, C₁₋₈ sulfonyl, optionally substitutedC₂₋₄ alkenyl, optionally substituted C₂₋₄ alkynyl, optionallysubstituted C₁₋₄ alkoxy, C₀₋₈ alkylamino, optionally substituted C₄₋₁₄aryl, optionally substituted C₄₋₁₄ aryloxy, C₁₋₅ oxycarbonyl, C₁₋₅carbonyloxy, optionally substituted C₃₋₆ heterocycloalkyl, optionallysubstituted C₁₋₁₀ heteroaryl, hydroxy, and nitro;R₃ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, andoptionally substituted C₃₋₆ heterocycloalkyl;R₄ is selected from the group consisting of methyl and trifluoromethyl;R₅ is selected from the group consisting of hydrogen, halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₄ alkenyl, andoptionally substituted C₃₋₈ cycloalkyl;R₆ is selected from the group consisting of hydrogen, halo, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₂₋₄ alkenyl, andoptionally substituted C₃₋₈ cycloalkyl; orR₅ and R₆ are taken together to form an optionally substituted C₁-C₃alkylenyl; orR₄ and R₅ are taken together to form an optionally substituted C₁-C₃alkylenyl; orR₄ and R₆ are taken together to form an optionally substituted C₁-C₃alkylenyl; andR₇ is selected from the group consisting of hydrogen, C₀₋₈ alkylamino,C₁₋₇ amido, C₁₋₉ amide, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido, C₀₋₆sulfonylamino, C₁₋₅ ureido, optionally substituted C₁₋₄ alkyl,optionally substituted C₁₋₄ alkoxy, cyano, halo, hydroxyl, nitro, C₁₋₅oxycarbonyl, and C₁₋₈ sulfonyl;R₈ is, each time taken, independently selected from the group consistingof hydrogen, optionally substituted C₁₋₆ alkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₄₋₁₄ aryl, optionallysubstituted C₃₋₆ heterocycloalkyl, and optionally substituted C₁₋₁₀heteroaryl;R₉ is, each time taken, independently selected from the group consistingof hydrogen, optionally substituted C₁₋₆ alkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₄₋₁₄ aryl, optionallysubstituted C₃₋₆ heterocycloalkyl, and optionally substituted C₁₋₁₀heteroaryl;R₁₀ is, each time taken, independently selected from the groupconsisting of optionally substituted C₁₋₆ alkyl, optionally substitutedC₃₋₈ cycloalkyl, optionally substituted C₄₋₁₄ aryl, and optionallysubstituted C₃₋₆ heterocycloalkyl;R₁₁ is, each time taken, independently selected from the groupconsisting of hydrogen, optionally substituted C₁₋₆ alkyl, optionallysubstituted C₁₋₆ alkoxy, optionally substituted C₃₋₈ cycloalkyl,optionally substituted C₄₋₁₄ aryl, optionally substituted C₃₋₆heterocycloalkyl, optionally substituted C₁₋₁₀ heteroaryl, cyano, andnitro;R₁₂ is, each time taken, independently selected from the groupconsisting of optionally substituted C₁₋₆ alkyl and optionallysubstituted phenyl; andR₁₃ is, each time taken, independently selected from the groupconsisting of optionally substituted C₁₋₆ alkyl, optionally substitutedC₃₋₈ cycloalkyl, and optionally substituted C₄₋₁₄ aryl; or thepharmaceutically acceptable salts thereof.

The present invention also provides pharmaceutical compositions,comprising: a compound of formula I and a pharmaceutically acceptableexcipient.

The compounds of the invention are inhibitors of mTOR they are usefulfor the treatment of conditions associated with mTOR, including cancer.Thus, the invention provides methods of treating conditions associatedwith mTOR, comprising: administering to a patient in need thereof aneffective amount of a compound of formula I. Further, the presentinvention provides for the use of compounds of formula I, including forthe manufacture of a medicament, each specifically including for thetreatment of particular conditions associated with mTOR.

The present invention also provides an article of manufacture:comprising at least one compound of formula I and a label. Also providedare kits comprising at least one compound of the invention, a label, andapparatus for administration of the inhibitor.

The present invention also provides processes from making mTORinhibitors and intermediates thereof.

DETAILED DESCRIPTION OF THE INVENTION

The term “C₂₋₄ alkenyl” refers to a straight or branched alkenyl chainhaving from two to four carbon atoms and one or more carbon-carbondouble bonds, and includes ethylene, propylene, iso-propylene, butylene,iso-butylene, sec-butylene, and the like.

The term “optionally substituted C₂₋₄ alkenyl” refers to a C₂₋₄ alkenyloptionally having from 1 to 3 substituents independently selected fromthe group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl,cyano, C₃₋₈ cycloalkyl, halo, hydroxy, oxo, optionally substituted C₁₋₁₀heteroaryl, and optionally substituted phenyl.

The term “C₁₋₄ alkyl” refers to a straight or branched alkyl chainhaving from one to four carbon atoms.

The term “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄ alkyloptionally having from 1 to 5 substituents independently selected fromthe group consisting of C₂₋₄ alkenyl, optionally substituted C₁₋₄alkoxy, C₁₋₄ thioalkoxy, C₁₋₉ amide, C₀₋₈ alkylamino, C₁₋₅ oxycarbonyl,C₁₋₈ sulfonyl, cyano, optionally substituted C₃₋₈ cycloalkyl, C₃₋₈cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C₃₋₆heterocycloalkyl, optionally substituted C₁₋₁₀ heteroaryl, andoptionally substituted phenyl.

More particularly “optionally substituted C₁₋₄ alkyl” refers to a C₁₋₄alkyl optionally having from 1 to 5 substituents independently selectedfrom the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, C₀₋₈ alkylamino,C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo, hydroxy, C₃₋₆heterocycloalkyl optionally substituted on any ring nitrogen by C₁₋₄alkyl, C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

The term “C₁₋₆ alkyl” refers to a straight or branched alkyl chainhaving from one to six carbon atoms.

The term “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆ alkyloptionally having from 1 to 7 substituents independently selected fromthe group consisting of C₀₋₈ alkylamino, C₂₋₄ alkenyl, optionallysubstituted C₁₋₄ alkoxy, C₁₋₄ thioalkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl,C₁₋₈ sulfonyl, cyano, optionally substituted C₃₋₈ cycloalkyl, halo,hydroxy, oxo, optionally substituted C₁₋₁₀ heteroaryl, optionallysubstituted C₃₋₆ heterocycloalkyl, optionally substituted C₁₋₁₀heteroaryl, and optionally substituted phenyl.

More particularly “optionally substituted C₁₋₆ alkyl” refers to a C₁₋₆alkyl optionally having from 1 to 7 substituents independently selectedfrom the group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, C₀₋₈ alkylamino,C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, halo, hydroxy, C₃₋₆heterocycloalkyl optionally substituted on any ring nitrogen by C₁₋₄alkyl, C₁₋₁₀ heteroaryl, and optionally substituted phenyl.

The term “C₁-C₃ alkylenyl” refers to a C₁-C₃ alkylene having anattachment at each end and consists of —CH₂—, —CH₂CH₂—, and —CH₂CH₂CH₂—.

The term “optionally substituted C₁-C₃ alkylenyl” refers to a C₁-C₃alkylene optionally having from 1 to 2 C₁₋₆ alkyl groups.

The term “C₁₋₈ sulfonyl” refers to a sulfonyl linked to a C₁₋₆ alkylgroup, C₃₋₈ cycloalkyl, or an optionally substituted phenyl.

The term “C₁₋₄ alkoxy” refers to a C₁₋₄ alkyl attached through an oxygenatom.

The term “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄ alkoxyoptionally having from 1 to 6 substituents independently selected fromthe group consisting of C₂₋₄ alkenyl, C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅oxycarbonyl, cyano, optionally substituted C₃₋₈ cycloalkyl, halo,hydroxy, optionally substituted C₁₋₁₀ heteroaryl, and optionallysubstituted phenyl. While it is understood that where the optionalsubstituent is C₁₋₄ alkoxy, cyano, halo, or hydroxy then the substituentis generally not alpha to the alkoxy attachment point, the term“optionally substituted C₁₋₄ alkoxy” includes stable moieties andspecifically includes trifluoromethoxy, difluoromethoxy, andfluoromethoxy.

More particularly “optionally substituted C₁₋₄ alkoxy” refers to a C₁₋₄alkoxy optionally having from 1 to 6 substituents independently selectedfrom the group consisting of C₁₋₄ alkoxy, cyano, C₃₋₈ cycloalkyl, halo,hydroxy, and phenyl.

The term “C₂₋₄ alkynyl” refers to a straight or branched alkynyl chainhaving from two to six carbon atoms and one or more carbon-carbon triplebonds.

The term “optionally substituted C₂₋₄ alkynyl” refers to a C₂₋₆ alkynyloptionally having from 1 to 3 substituents independently selected fromthe group consisting of C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₅ oxycarbonyl,cyano, C₃₋₈ cycloalkyl, halo, hydroxy, oxo, optionally substituted C₁₋₁₀heteroaryl, and optionally substituted phenyl.

The term “C₁₋₉ amide” refers to an amide having two groups independentlyselected from the group consisting of hydrogen, C₁₋₄ alkyl, andoptionally substituted phenyl, for example, —CONH₂, —CONHCH₃, and—CON(CH₃)₂.

The term “C₁₋₇ amido” refers to a —NHC(O)R group in which R is selectedfrom the group consisting of hydrogen, C₁₋₆ alkyl, and optionallysubstituted phenyl.

The term “C₁₋₅ carbamoyl” refers to an O- or N-linked carbamate having aterminal C₁₋₄ alkyl.

The term “C₁₋₅ ureido” refers to a urea optionally having a C₁₋₄ alkyl.

The term “C₀₋₈ alkylamino” refers to an amino optionally having one ortwo C₁₋₄ alkyl.

The term “C₄₋₁₄ aryl” refers to a monocyclic and polycyclic unsaturated,conjugated hydrocarbon having aromatic character and having four tofourteen carbon atoms, and includes phenyl, biphenyl, indenyl,cyclopentyldienyl, fluorenyl, and naphthyl.

More particularly “C₄₋₁₄ aryl” refers to phenyl.

The term “optionally substituted C₄₋₁₄ aryl” refers to a C₄₋₁₄ aryloptionally having 1 to 5 substituents independently selected from thegroup consisting of C₀₋₈ alkylamino, C₁₋₇ amido, C₁₋₉ amide, C₁₋₅carbamoyl, C₁₋₆ sulfonylamido, C₀₋₆ sulfonylamino, C₁₋₅ ureido, C₁₋₄alkyl, C₁₋₄ alkoxy, cyano, halo, hydroxyl, C₁₋₅ oxycarbonyl,trifluoromethyl, trifluoromethoxy, and C₁₋₈ sulfonyl.

More particularly “optionally substituted C₄₋₁₄ aryl” refers to a C₄₋₁₄aryl optionally having 1 to 5 substituents independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halo, C₁₋₅oxycarbonyl, trifluoromethyl, and trifluoromethoxy.

The term “C₄₋₁₄ aryloxy” refers to a C₄₋₁₄ aryl attached through anoxygen atom.

The term “optionally substituted C₄₋₁₄ aryloxy” refers to a C₄₋₁₄aryloxy optionally having 1 to 5 substituents independently selectedfrom the group consisting of C₀₋₈ alkylamino, C₁₋₄ alkyl, C₁₋₄ alkoxy,cyano, halo, hydroxyl, nitro, C₁₋₈ sulfonyl, and trifluoromethyl.

The term “C₁₋₅ oxycarbonyl” refers to an oxycarbonyl group (—CO₂H) andC₁₋₄ alkyl ester thereof.

The term “C₁₋₅ carbonyloxy” refers to a carbonyloxy group (—O₂CR), forexample acetoxy.

The term “C₃₋₈ cycloalkyl” refers to an alkyl ring having from three toeight carbon atoms, and includes cyclopropyl, 2-methyl cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, and the like.

The term “optionally substituted C₃₋₈ cycloalkyl” refers to a C₃₋₈cycloalkyl optionally having from 1 to 6 substituents independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₂₋₄ alkenyl, optionally substituted C₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₇amido, C₀₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, C₃₋₈ cycloalkyl, C₃₋₈cycloalkoxy, halo, hydroxy, nitro, oxo, optionally substituted C₁₋₁₀heteroaryl, and optionally substituted phenyl.

More particularly “optionally substituted C₃₋₈ cycloalkyl” refers to aC₃₋₈ cycloalkyl optionally having from 1 to 3 substituents independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, andhydroxy.

The term “C₃₋₈ cycloalkylC₁₋₄ alkyl” refers to a C₁₋₄ alkyl substitutedby a C₃₋₈ cycloalkyl. It is understood that the C₃₋₈ cycloalkyl can beattached in any manner, including pendant, fused, or spiro.

The term “C₃₋₈ cycloalkoxy” refers to a C₃₋₈ cycloalkyl attached throughan oxygen atom.

The terms “halogen” and “halo” refers to a chloro, fluoro, bromo or iodoatom.

The term “C₃₋₆ heterocycloalkyl” refers to a 4 to 10 membered monocyclicsaturated or partially (but not fully) unsaturated ring having one tofour heteroatoms selected from the group consisting of nitrogen, oxygen,and sulfur. It is understood that where sulfur is included that thesulfur may be either —S—, —SO—, and —SO₂—. For example, but notlimiting, the term includes azetidine, pyrrolidine, piperidine,piperazine, morpholine, thiomorpholine, oxetane, dioxolane,tetrahydropyran, tetrahydrothiopyran, dioxidotetrahydrothiopyran,tetrahydrofuran, hexahydropyrimidine, tetrahydropyrimidine,dihydroimidazole, and the like. It is understood that a C₃₋₆heterocycloalkyl can be attached as a substituent through a ring carbonor a ring nitrogen atom.

More particularly “C₃₋₆ heterocycloalkyl” is selected from the groupconsisting of pyrrolidine, piperidine, piperazine, morpholine, oxetane,tetrahydropyran, tetrahydrothiopyran, dioxidotetrahydrothiopyran, andtetrahydrofuran.

The term “optionally substituted C₃₋₆ heterocycloalkyl” refers to a C₃₋₆heterocycloalkyl optionally substituted on the ring carbons with 1 to 4substituents independently selected from the group consisting ofoptionally substituted C₁₋₄ alkyl, C₂₋₄ alkenyl, optionally substitutedC₁₋₄ alkoxy, C₁₋₉ amide, C₁₋₇ amido, C₀₋₈ alkylamino, C₁₋₅ oxycarbonyl,cyano, optionally substituted C₃₋₈ cycloalkyl, C₃₋₈ cycloalkoxy, halo,hydroxy, nitro, oxo, and optionally substituted phenyl; and optionallysubstituted on any ring nitrogen with a substituent independentlyselected from the group consisting of optionally substituted C₁₋₄ alkyl,C₂₋₄ alkenyl, C₃₋₈ cycloalkyl, optionally substituted C₃₋₆heterocycloalkyl, optionally substituted C₁₋₁₀ heteroaryl, andoptionally substituted phenyl.

More particularly “optionally substituted C₃₋₆ heterocycloalkyl” refersto a C₃₋₆ heterocycloalkyl optionally substituted on the ring carbonswith 1 to 4 substituents independently selected from the groupconsisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, halo, and hydroxy and optionallysubstituted on any ring nitrogen with a C₁₋₄ alkyl.

The term “C₁₋₁₀ heteroaryl” refers to a five to twelve memberedmonocyclic and polycyclic having unsaturated, conjugated ring(s) havingaromatic character and having one to ten carbon atoms and one or more,typically one to four, heteroatoms selected from the group consisting ofnitrogen, oxygen, and sulfur. For example, but not limiting, the termincludes azepine, diazepine, furan, thiophene, pyrrole, imidazole,isothiazole, isoxazole, oxadiazole, oxazole, pyrazine, pyrazole,pyridazine, pyridine, pyrimidine, thiazole, thiadiazole, triazole,tetrazole, benzazepine, benzodiazepine, benzofuran, benzothiophene,benzimidazole, imidazopyridine, pyrazolopyridine, pyrrolopyridine,quinazoline, thienopyridine, indolizine, imidazopyridine, quinoline,isoquinoline, indole, isoindole, benzoxazole, benzoxadiazole,benzopyrazole, benzothiazole, and the like. It is understood that aC₁₋₁₀ heteroaryl can be attached as a substituent through a ring carbonor a ring nitrogen atom where such an attachment mode is available, forexample for an indole, imidazole, azepine, triazole, pyrazine, etc.

More particularly “C₁₋₁₀ heteroaryl” is selected from the groupconsisting of furan, thiophene, pyrrole, imidazole, isothiazole,isoxazole, oxadiazole, oxazole, pyrazine, pyrazole, pyridazine,pyridine, pyrimidine, thiazole, thiadiazole, and triazole.

The term “optionally substituted C₁₋₁₀ heteroaryl” refers to a C₁₋₁₀heteroaryl optionally having 1 to 5 substituents on carbon independentlyselected from the group consisting of C₁₋₇ amido, C₀₋₈ alkylamino, C₁₋₉amide, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido, C₀₋₆ sulfonylamino, C₁₋₅ureido, optionally substituted C₁₋₄ alkyl, optionally substituted C₁₋₄alkoxy, cyano, halo, hydroxyl, oxo, nitro, C₁₋₅ oxycarbonyl, and C₁₋₈sulfonyl and optionally having a substituent on each nitrogenindependently selected from the group consisting of optionallysubstituted C₁₋₄ alkyl, C₁₋₈ sulfonyl, optionally substituted C₃₋₆heterocycloalkyl, and optionally substituted phenyl.

More particularly “optionally substituted C₁₋₁₀ heteroaryl” refers to aC₁₋₁₀ heteroaryl optionally having 1 to 5 substituents on carbonindependently selected from the group consisting of C₁₋₇ amido, C₀₋₈alkylamino, C₁₋₉ amide, C₁₋₅ carbamoyl, C₁₋₆ sulfonylamido, C₀₋₆sulfonylamino, C₁₋₅ ureido, C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano, halo,hydroxyl, oxo, C₁₋₅ oxycarbonyl, trifluoromethyl, trifluoromethoxy, andC₁₋₈ sulfonyl and optionally having a substituent on each nitrogen aC₁₋₄ alkyl.

Even more particularly “optionally substituted C₁₋₁₀ heteroaryl” refersto a C₁₋₁₀ heteroaryl optionally having 1 to 5 substituentsindependently selected from the group consisting of C₁₋₄ alkyl, C₁₋₄alkoxy, cyano, halo, C₁₋₅ oxycarbonyl, trifluoromethyl, andtrifluoromethoxy.

The term “oxo” refers to an oxygen atom having a double bond to thecarbon to which it is attached to form the carbonyl of a ketone oraldehyde. It is understood that as the term is used herein oxo refers todoubly bonded oxygen attached to the group which has the oxosubstituent, as opposed to the oxo group being pendant as a formylgroup. For example, an acetyl radical is contemplated as an oxosubstituted alkyl group and a pryidone radical is contemplated as an oxosubstituted C₁₋₁₀ heteroaryl.

The term “C₁₋₁₀ heteroaryloxy” refers to a C₁₋₁₀ heteroaryl attachedthrough an oxygen.

The term “optionally substituted C₁₋₁₀ heteroaryloxy” refers to a C₁₋₁₀heteroaryl optionally having 1 to 5 substituents on carbon independentlyselected from the group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, cyano,halo, hydroxyl, nitro, oxo, C₁₋₈ sulfonyl, and trifluoromethyl andoptionally having substituents on each nitrogen independently selectedfrom the group consisting of optionally substituted C₁₋₄ alkyl, C₁₋₈sulfonyl, and optionally substituted phenyl.

The term “optionally substituted phenyl” refers to a phenyl groupoptionally having 1 to 5 substituents independently selected from thegroup consisting of C₂₋₄ alkenyl, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amide,C₀₋₈ alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxyl, nitro, C₁₋₈sulfonyl, and trifluoromethyl.

More particularly “optionally substituted phenyl” refers to a phenylgroup optionally having 1 to 5 substituents independently selected fromthe group consisting of C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₉ amide, C₀₋₈alkylamino, C₁₋₅ oxycarbonyl, cyano, halo, hydroxyl, nitro, andtrifluoromethyl.

The term “C₁₋₆ sulfonylamido” refers to a —NHS(O)₂—R group wherein R isC₁₋₆ alkyl.

The term “C₀₋₆ sulfonylamino” refers to a —S(O)₂NH—R group wherein R isselected from the group consisting of hydrogen and is C₁₋₆ alkyl.

The term “C₁₋₄ thioalkoxy” refers to a C₁₋₄ alkyl attached through asulfur atom.

The term “pharmaceutically acceptable salt” refers to salts ofpharmaceutically acceptable organic acids and bases or inorganic acidsand bases. Such salts are well known in the art and include thosedescribed in Journal of Pharmaceutical Science, 66, 2-19 (1977).Examples are the hydrochloride and mesylate salts.

The term “substituted,” including when used in “optionally substituted”refers to one or more hydrogen radicals of a group having been replacedwith non-hydrogen radicals (substituent(s)). It is understood that thesubstituents may be either the same or different at every substitutedposition and may include the formation of rings. Combinations of groupsand substituents envisioned by this invention are those that are stableor chemically feasible.

The term “stable” refers to compounds that are not substantially alteredwhen subjected to conditions to allow for their production. In anon-limiting example, a stable compound or chemically feasible compoundis one that is not substantially altered when kept at a temperature of40° C. or less, in the absence of moisture or other chemically reactiveconditions, for about a week.

It is understood that, where the terms defined herein mention a numberof carbon atoms, that the mentioned number refers to the mentioned groupand does not include any carbons that may be present in any optionalsubstituent(s) thereon.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as isomers. All mixtures of stereoisomers, inany ratio, and specific geometric isomers, enantiomers, anddiastereomers of the compounds of the invention are contemplated to bewithin the scope of the present invention.

The skilled artisan will appreciate that certain of the compounds of thepresent invention exist as tautomers. All tautomeric forms the compoundsof the invention are contemplated to be within the scope of the presentinvention.

The term “compounds of the invention” include the embodiment of formulaI and the other embodiments and examples described herein.

(a) One embodiment relates to compounds of formula I wherein R₄ ismethyl.

(b) Another embodiment relates to compounds of formula I wherein R₄ istrifluoromethyl

(c) Another embodiment relates to compounds of formula I and embodiments(a) and (b) wherein Ar is C₄₋₁₄ aryl.

(d) Another embodiment relates to compounds of formula I and embodiments(a) and (b) wherein Ar is phenyl.

(e) Another embodiment relates to compounds of formula I and embodiments(a) and (b) wherein Ar is C₁₋₁₀ heteroaryl.

(f) Another embodiment relates to compounds of formula I and embodiments(a) and (b) wherein Ar is C₁₋₁₀ heteroaryl selected from the groupconsisting of furan, thiophene, imidazole, oxazole, pyrazine,pyridazine, pyridine, pyrimidine, and thiazole.

(g) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), and (f) wherein G₁ is N.

(h) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), and (f) wherein G₁ is CR₇.

(i) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), and (f) wherein G₁ is CR₇ and R₇ is selectedfrom the group consisting of hydrogen, halo, C₀₋₈ alkylamino, C₁₋₇amido, C₁₋₉ amide, C₁₋₅ carbamoyl, C₁₋₅ ureido, cyano, and hydroxyl.

(j) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), and (f) wherein G₁ is CR₇ and R₇ is selectedfrom the group consisting of hydrogen, halo, cyano, and hydroxyl.

(k) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), and (j) wherein G₂ is C═O.

(l) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), and (j) wherein G₂ is CH₂.

(m) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l) whereinR₃ is selected from the group consisting of optionally substituted C₁₋₆alkyl, optionally substituted C₃₋₆ heterocycloalkyl, and optionallysubstituted C₃₋₈ cycloalkyl.

(n) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l) whereinR₃ is C₁₋₆ alkyl optionally substituted with 1 to 5 substituentsselected from the group consisting of halo, hydroxy, C₁₋₄ alkoxy, C₃₋₈cycloalkyl, and C₃₋₆ heterocycloalkyl selected from the group consistingof piperidine, piperazine, morpholine, oxetane, tetrahydropyran, andtetrahydrofuran optionally substituted on any ring nitrogen by C₁₋₄alkyl.

(o) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l) whereinR₃ is C₁₋₆ alkyl.

(p) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l) whereinR₃ is C₃₋₆ heterocycloalkyl selected from the group consisting ofpiperidine, piperazine, morpholine, oxetane, tetrahydropyran,tetrahydrothiopyran, dioxidotetrahydrothiopyran, and tetrahydrofuran andoptionally substituted on any ring nitrogen by C₁₋₄ alkyl.

(q) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l) whereinR₃ is C₃₋₈ cycloalkyl.

(r) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), and (l) whereinR₃ is C₃₋₈ cycloalkylC₁₋₄ alkyl.

(s) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), and (r) wherein R₂ is hydrogen.

(t) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), and (s) wherein R₅ C₁₋₆ alkyl and R₆ is hydrogen.

(u) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), and (s) wherein R₅ is hydrogen and R₆ is C₁₋₆ alkyl.

(v) Another embodiment relate to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), and (s) wherein R₅ methyl and R₆ is hydrogen.

(w) Another embodiment relate to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), and (s) wherein R₅ is hydrogen and R₆ is methyl.

(x) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), and (s) wherein R₅ is hydrogen and R₆ is hydrogen.

(y) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), and (s) wherein R₅ and R₆ are taken together to form—CH₂CH₂—.

(z) Another embodiment relates to compounds of formula I and embodiments(a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n),(o), (p), (q), (r), (s), (t), (u), (v), (w), (x), and (y) wherein R₁ is,each time taken, independently selected from the group consisting ofhalo, cyano, C₁₋₆ alkyl, trifluoromethyl, C₁₋₄ alkoxy, trifluoromethoxy,nitro, —NHC(O)NR₈R₉, —NHC(O)OR₁₀, and —NH(SO₂)NHR₈.

(aa) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is selected from thegroup consisting of —NHC(O)NR₈R₉, —NHC(O)OR₁₀, and —NH(SO₂)NHR₈.

(bb) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is —NHC(O)NR₈R₉ and R₈ ishydrogen and R₉ is selected from the group consisting of C₁₋₄ alkyl,C₃₋₈ cycloalkylC₁₋₄ alkyl, and C₃₋₈ cycloalkyl.

(cc) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), and (x) wherein mis at least 1 and at least one of R₁ is —NHC(O)NR₈R₉ and R₈ is hydrogenand R₉ is C₁₋₄ alkyl.

(dd) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is —NHC(O)NR₈R₉ and R₈ ishydrogen and R₉ is C₃₋₈ cycloalkylC₁₋₄ alkyl.

(ee) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is —NHC(O)NR₈R₉ and R₈ ishydrogen and R₉ is C₃₋₈ cycloalkyl.

(ff) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is selected from thegroup consisting of —NHC(O)NR₈R₉ and R₈ is hydrogen and R₉ is selectedfrom the group consisting of methyl and ethyl.

(gg) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is selected from thegroup consisting of —NHC(O)NR₈R₉ and R₈ is hydrogen and R₉ is C₃₋₈cycloalkylC₁₋₄ alkyl selected from the group consisting ofmethylcyclopropyl, methylcyclobutyl, and methylcyclopentyl.

(hh) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), and (z)wherein m is at least 1 and at least one of R₁ is selected from thegroup consisting of —NHC(O)NR₈R₉ and R₈ is hydrogen and R₉ is C₃₋₈cycloalkyl selected from the group consisting of cyclopropyl,cyclobutyl, and cyclopentyl.

(ii) Another embodiment relates to compounds of formula I andembodiments (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l),(m), (n), (o), (p), (q), (r), (s), (t), (u), (v), (w), (x), (y), (z),(aa), (bb), (cc), (dd), (ee), (ff), (gg), and (hh) wherein m is 1.

The compounds of the invention can be prepared by a variety ofprocedures, some of which are described below. All substituents, unlessotherwise indicated, are as previously defined. The products of eachstep can be recovered by conventional methods including extraction,evaporation, precipitation, chromatography, filtration, trituration,crystallization, and the like. The procedures may require protection ofcertain groups, for example hydroxy, amino, or carboxy groups tominimize unwanted reactions. The selection, use, and removal ofprotecting groups are well known and appreciated as standard practice,for example T. W. Greene and P. G. M. Wuts in Protective Groups inOrganic Chemistry (John Wiley and Sons, 1991).

Scheme A, step 1a, depicts the reaction of an appropriate compound offormula (a) with an appropriate compound of formula (b) to give acompound of formula (c). An appropriate compound of formula (a) is onein which G₁ is as desired in the final compound of formula I, R₂ is asdesired in the final compound of formula I, R_(3′) is a protecting groupor R₃ as desired in the final compound of formula I or gives rise to R₃as desired in the final compound of formula I, and X and X₁ are leavinggroups, including halogens, particularly as chloro and bromo. Anappropriate compound of formula (b) is one in which R is hydrogen orforms and ester, such as a C₁₋₄ alkyl, R₅ and R₆ are as desired in thefinal compound of formula I, and R_(4′) is hydrogen or R₄ as desired inthe final compound of formula I.

Such reactions are well understood and appreciated. For example, such areaction is generally carried out in a solvent, such as DMSO, THF,dimethylformamide, dimethylacetamide, and the like. The reaction iscarried out with the use of a suitable base, such as alkali metalhydroxides, such as sodium hydroxide, and alkali metal alkoxides, suchas sodium alkoxides and potassium alkoxides, alkali metal carbonates,such as sodium carbonate and potassium carbonate and amine bases, suchdiisopropylethylamine (DIPEA), triethylamine, pyridine, and the like.The reaction is typically carried out at temperatures of from 0° C. to100° C. The reaction typically requires 1 to 72 hours.

Scheme A, step 1b, depicts the reaction of an appropriate compound offormula (g) with an appropriate compound of formula (b) to give acompound of formula (I). An appropriate compound of formula (g) is onein which G₁ is as desired in the final compound of formula I and X andX₁ are leaving groups, including halogens, particularly as chloro andbromo. An appropriate compound of formula (b) is as described in SchemeA, step 1a. Such reactions are well understood and appreciated and arecarried out, for example as described above in Scheme A, step 1a.

Scheme A, step 2b, depicts the reduction of the nitro group of acompound of formula (i) and cyclization to give a compound of formula(c) in which R_(3′) is hydrogen. Such reduction reactions are well knownin the art. Such cyclization reactions are also well known in the art.

Scheme A, step 1c, depicts the reaction of an appropriate compound offormula (m) with an appropriate compound of formula (a) to give acompound of formula (n). An appropriate compound of formula (m) is onein which Pg₁ is a protecting group, R₅ and R₆ are as desired in thefinal compound of formula I, and R_(4′) is hydrogen or R₄ as desired inthe final compound of formula I. An appropriate compound of formula (a)is as described in Scheme A, step 1a. Such amide forming reactions arewell understood and appreciated.

Scheme a, step 2c, depicts the deprotection and cyclization of acompound of formula (n) to give a compound of formula (c). The use andremoval of suitable protecting groups is well known and appreciated inthe art. Cyclization reactions are also well known and also described inScheme A, step 1a. Once obtained a compound of formula (c) can beelaborated as further described in Scheme A.

Scheme A, step 3, depicts the reaction of a compound of formula (c) inwhich R_(3′) is hydrogen with an appropriate alkylating reagent to givea compound of formula (d). An appropriate alkylating reagent is one ofthe formula R₃—X₃ where R₃ is as desired in the final compound offormula I and X₃ is a suitable leaving group, for example a halogen,particularly chloro, bromo, or iodo, or a sulfonate, for exampletrifluoromethanesulfonate, toslylate, or nosylate.

For example, such a reaction is generally carried out in a solvent, suchas DMSO, THF, dimethylformamide, dimethylacetamide, pyridine, and thelike. The reaction is carried out with the use of a suitable base, suchas alkali metal alkoxides, such as sodium alkoxides, alkali metalcarbonates, such as potassium carbonate, and stronger bases such aslithium diisopropylamide and lithium hexamethyldisilazide, and the like.The reaction is typically carried out at temperatures of from 0° C. to100° C. The reaction typically requires 1 to 72 hours.

Scheme A, steps 4, depicts the reaction of a compound of formula (c) inwhich R_(3′) is a protecting group and R_(4′) is hydrogen or a compoundof formula (d) in which R_(4′) is hydrogen and R₃ is as desired in thefinal product of formula I to give a compound of formula (e).Appropriate reagents are methyl halides, such as methyl iodide, dimethylsulfate, methyl sulfonates and trifluoromethyl transfer reagents. It isunderstood that compounds of formula (e) in which R₃ is hydrogen can bereadily prepared by the method of step 3 by the use protecting groupswhich can be removed after step 4, 5, or 6.

For example, such reactions are generally carried out in a suitablesolvent such as DMSO, DMF, THF and the like and may be carried out usinga suitable base, such as alkali metal hydroxides, such as sodiumhydroxide, and alkali metal alkoxides, such as sodium alkoxides, and thelike. The reaction typically is carried out at temperatures of from −20°C. to 20° C. and require about 1 hour to 3 days.

Scheme A, steps 5, depicts the reduction of amides (c) in which R₃ ishydrogen or amides (e) to give an amine for formula (f). Such reactionsare well known and can be carried out using lithium aluminum hydride,catalytic hydrogenation, and borane reagents as is well known in theart. Suitable compounds of formula (c) or (e) are those in which R_(4′)is R₄ as desired in the final compound of formula I.

It is understood that a compound of formula (f) in which R₃ is hydrogen,in a step not shown, can be alkylated to give a compound of formula (f)in which R₃ is not hydrogen. Such alkylations can be accomplished by theuse of alkylating agents or by reductive amination.

For example, alkylations of such an amine are carried out with anappropriate alkylating reagent. An appropriate alkylating reagent is oneof the formula R₃—X₂ where R₃ is as desired in the final compound offormula I and X₂ is a suitable leaving group, such as a halogen,particularly chlorine, bromine or iodine, or a sulfonate, such asmethanesulfonate or p-toluenesulfonate. Such reactions are generallycarried out in a solvent, such as ethyl acetate, tetrahydrofuran,dimethylformamide, DMSO, or acetonitrile and with a base, such aspotassium carbonate, sodium carbonate, sodium bicarbonate,triethylamine, or diisopropyethylamine. Such reactions generally arecarried out at a temperature of from room temperature to the refluxtemperature of the chosen solvent and typically require 1 hour to 2days.

For reductive alkylations are carried out using a ketone or aldehydewhich gives rise to R₃ as desired in the final compound of formula I.For example, reductive aminations are carried out under a variety ofconditions using reducing agents, such as sodium borohydride, sodiumtriacetoxyborohydride, zinc/hydrochloric acid, zinc borohydride, and thelike. When using sodium cyanoborohydride the reaction is carried out ina solvent, such as methanol, ethanol, isopropanol, and water or mixturesthereof. As is well known in the art, it may be advantageous to monitorand adjust the pH during such reactions. Typically the reaction iscarried out at temperatures of from about 0° C. to about 60° C. andtypically require from about 1 to about 24 hours.

Alternately, such reductive amination can be carried out byhydrogenation over a catalyst. A variety of catalysts are suitable forthis purpose, including palladium, platinum, and nickel catalysts. Suchhydrogenations are carried out in a suitable solvent such as ethylacetate, ethanol, methanol, isopropanol, and the like and are carriedout at pressure ranging from atmospheric to about 300 psi (2068kPascals) and temperatures of from room temperature to about 100° C.

Scheme A, steps 6, depicts the reaction of a compound of formula (e) or(f) with an appropriate —Ar(R1)m transfer reagent to give compound offormula I. An appropriate —Ar(R₁)_(m) transfer reagent is one in whichAr, R₁, and m are as desired in the formula I or R₁ give rise to a groupas desired in the final compound of formula I. Such reactions are wellknown and include metal catalyzed carbon-carbon bond forming reactionssuch as the Suzuki coupling. For example, a compound of formula (e) or(f) a reacted with an appropriate borane compound, such as(HO)₂B—Ar(R₁)_(m) to give a compound of formula I.

It will be recognized by one of ordinary skill in the art that the stepsin Scheme A may be varied to provide compounds of formula I. Inparticular, the order of the steps required to produce the compounds offormula I is dependent upon the particular compound being synthesized,the starting compound, and the relative lability of the substitutedmoieties. For example, a compound of formula (a) can undergo step 6 toprovide a compound of formula (a) in which X is —Ar(R₁)_(m) which isfurther elaborated to give a compound of formula I or a compound offormula (n) is reduced and then cyclized to give a compound of formula(f) directly.

It is also understood that some compounds of formula I may be elaboratedto other compounds of formula I, in an additional steps not shown. Forexample, a compound of formula I in which R₁ or R₂ is halogen, generallybromo, can undergo a variety of reactions to give compound in which R₁or R₂ is other than halogen. Compounds of formula I may be elaborated ina variety of other ways. Such reactions include hydrolysis, oxidation,reduction, alkylation, amidations, sulfonations, alkynations,alkyenations, and the like. Also, in an optional step, not shown, thecompounds of formula I can be converted to pharmaceutically acceptablesalts by methods well known and appreciated in the art.

Scheme B, step 1, depicts the protection of an appropriate compound offormula (o) to give a compound of formula (p). An appropriate compoundof formula (o) is one in which R₄ is as desired in the final compound offormula I. In a compound of formula (p), Pg₁ is a suitable protectinggroup, generally an amide or carbamate protecting group, includingbenzamine, acetamide, t-butoxycarbonyl, benzyloxycarbonyl, and the like.The use of protecting groups is well understood and appreciated.

Scheme B, step 2, depicts the reaction of a compound of formula (p) withan appropriate cyclizing reagent to give a compound of formula (q).Examples of appropriate cyclizing reagent include chloroacetyl chloride.Such cyclization reactions can be used to give a compound of formula (r)directly by using cyclization reagents such as dibromoethane to give acompound of formula (r) directly.

Cyclization reactions such as that depicted in Scheme B, step 2, can becarried out under a variety of conditions typically used for amideformation.

Scheme B, steps 3, depicts the reduction of an amide of a compound offormula (q) to give a compound of formula (r). The reduction of amidesto giver amines is well known in the art. Such reactions are well knownand can be carried out using lithium aluminum hydride, catalytichydrogenation, and borane reagents as is well known in the art.

Scheme B, steps 4, depicts the oxidation of an alcohol of formula (r) togive an acid of formula (m) in which R₅ and R₆ are hydrogen. Suchoxidations are well known.

Example 11-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

A round-bottomed flask equipped with a magnetic stirrer was added2,4-dichloropyrimidin-5-amine (1.89 g, 11.52 mmol), DIPEA (8.05 ml, 46.1mmol), morpholine-3-carboxylic acid (1.66 g, 12.68 mmol), and DMSO (5ml). The reaction was stirred at 100° C. overnight. The reaction mixturewas poured into water and extracted with EtOAc 3 times. The pH of theaqueous layer was adjusted (about 5) with 10% citric acid and extractedagain with EtOAc. The combined organic layer dried over MgSO₄, filtered,and concentrated in vacuo to furnish a tan solid. The solid wastriturated in diethyl ether containing a small amount of EtOH, filtered,and dried to give2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one:1.95 g (70.3%). MS [M+H] found 241.

To a round-bottomed flask equipped with a magnetic stirrer was added2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (800mg, 3.32 mmol), DMSO (5 ml), sodium 2-methylpropan-2-olate (351 mg, 3.66mmol). The reaction mixture was cooled to 0° C. and(bromomethyl)cyclopropane (0.372 ml, 3.66 mmol) was added in DMSO (1mL). The reaction was removed from the ice-bath and stirred at 20° C.for 16 hours. The heterogeneous suspension was added to water (10 mL) togive a precipitate, which was collected by filtration, was successivelywashed with water, a small amount of ethanol and diethyl ether. Thecollected solid was dried in-vacuo to afford2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(746 mg, 2.53 mmol, 76% yield) as a off white solid. MS [M+H] found 295.

To a round-bottomed flask equipped with a magnetic stirrer was added2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(745 mg, 2.53 mmol), DMSO (10 ml), iodomethane (0.189 ml, 3.03 mmol).The suspension was cooled to 0° C. and sodium 2-methylpropan-2-olate(292 mg, 3.03 mmol) was added. The reaction was removed from theice-bath and stirred at 20° C. for 16 hours. The reaction solution waspoured into water, extracted with ethyl acetate 3 times and the organiclayer washed with saturated NaCl. The organic layer was collected, driedwith Na₂SO₄, filtered and the filtrate concentrated in vacuo to furnisha light-brown solid. The solid was washed with a small amount of ethanolfollowed by diethyl ether to afford2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(641 mg, 2.228 mmol, 82% yield) as white solid. MS [M+H] found 309.

To a microwave vial equipped with a magnetic stirrer was added2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(88 mg, 0.285 mmol), 1,4-dioxane (2 ml),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(118 mg, 0.428 mmol), NaHCO₃ (saturated, 0.491 mL), and PdCl₂(dppf) (209mg, 0.285 mmol). The reaction was irradiated in the microwave at 100° C.for 40 min. The reaction solution was then poured into water, extractedwith ethyl acetate three times and the combined organic layers werewashed with water and then brine, then dried with Na₂SO₄, filtered, andthe filtrate concentrated in-vacuo to give a brown residue. The aqueouslayer was acidified with AcOH (pH about 5) and concentrated in-vacuo togive a grey residue. The combined residues were purified via preparativeLC/MS (45-50% gradient of 10 mmol NH₄HCO₃ in 20/80 (v/v)water/acetonitrile in 10 mmol NH₄HCO₃ in water, Phenomenex Gemini 5 μmC18, 75×30 mm column to give the title compound (54 mg, 0.128 mmol,44.8% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.25-0.57(m, 4H) 1.18 (m, 1H) 1.35 (s, 3H) 2.62-2.71 (m, 3H) 3.17-3.26 (m, 1H)3.54-3.65 (m, 1H) 3.68 (d, J=11.62 Hz, 1H) 3.81 (dd, J=14.53, 6.95 Hz,1H) 3.89-4.02 (m, 2H) 4.07 (dd, J=11.62, 3.54 Hz, 1H) 4.20 (dd, J=13.77,2.40 Hz, 1H) 6.07 (d, J=4.80 Hz, 1H) 7.49 (d, J=8.84 Hz, 2H) 8.19 (d,J=8.84 Hz, 2H) 8.36 (s, 1H) 8.72 (s, 1H). MS [M+H] found 423.

Example: 21-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylureaTFA salt

To a microwave vial equipped with a magnetic stirrer was added crude2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(140 mg, 0.453 mmol), DMA (2 ml),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(188 mg, 0.680 mmol), Na₂CO₃ (0.907 ml, 1.814 mmol, 2M), and PdCl₂(dppf)(16.59 mg, 0.023 mmol). The reaction was irradiated in the microwave at110° C. for 70 min. The reaction solution was poured into water,extracted with ethyl acetate 3 times and the organic layers washed withsaturated NaCl, dried with Na₂SO₄, filtered, and concentrated in-vacuoto give a residue. The residue was purified via preparative LC/MS elutedwith 25% of acetonitrile (containing 0.035% TFA) in water (containing0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column) to give thetitle compound (6 mg, 0.014 mmol, 3.13% yield) as a tan solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 0.22-0.58 (m, 4H) 1.16 (d, J=6.82 Hz, 1H) 1.35(s, 3H) 2.62-2.71 (m, 3H) 3.19-3.34 (m, 1H) 3.54-3.65 (m, 1H) 3.69 (d,J=11.62 Hz, 1H) 3.81 (dd, J=14.65, 7.07 Hz, 1H) 3.89-4.04 (m, 2H) 4.07(dd, J=11.37, 4.04 Hz, 1H) 4.14 (dd, J=5.68, 3.41 Hz, 1H) 6.11 (d,J=4.29 Hz, 1H) 7.51 (d, J=8.84 Hz, 2H) 8.19 (d, J=8.84 Hz, 2H) 8.35 (s,1H) 8.80 (s, 1H). MS [M+H] found 423.

Example: 3(R)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylureaand Example: 4(S)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

The product of Example 1 (20 mg) was separated by HPLC (Chiralpak AD-Hcolumn, flowrate=1.25 mL/min, eluting with 30% isopropanol in 10 mMaqueous NH₄OAc to give Isomer 1 (2 mg, t=1.33 min) and Isomer 2 (2 mg,t=3.48 min)

Example: 51-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylurea,TFA salt

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified preparative HPLC eluting with a gradientof 25-30% acetonitrile (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to afford (12mg, 8.49%) of a pale yellow solid. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm0.40-0.52 (m, 2H) 0.54-0.65 (m, 2H) 1.17 (t, J=7.2 Hz, 3H) 1.20-1.27 (m,1H) 1.71 (s, 3H) 3.26 (q, J=7.2 Hz, 2H) 3.50-3.62 (m, 1H) 3.64-3.72 (m,1H) 3.78-3.89 (m, 2H) 3.99 (dd, J=14.9, 7.1 Hz, 1H) 4.11-4.20 (m, 2H)4.66-4.77 (m, 1H) 7.63 (d, J=9.1 Hz, 2H) 8.04 (s, 1H) 8.12 (d, J=8.8 Hz,2H). MS [M+H] found 437.

Example: 61-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea,TFA salt

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC eluting with 25-30%acetonitrile (containing 0.035% TFA) in water (containing 0.05% TFA)using a Sunfire Prep 5 μm C18, 75×30 mm column) to afford (14 mg, 8.7%)as a pale yellow solid: ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.27-0.55 (m,6H) 0.58-0.70 (m, 2H) 1.18 (d, J=5.05 Hz, 1H) 1.40 (s, 3H) 2.56 (d,J=6.82 Hz, 1H) 3.30 (d, J=3.54 Hz, 1H) 3.61 (d, J=2.27 Hz, 1H) 3.70 (d,J=11.37 Hz, 1H) 3.84 (d, J=7.07 Hz, 1H) 3.89-4.12 (m, 3H) 4.20-4.35 (m,1H) 6.53 (br. s., 1H) 7.53 (d, J=8.59 Hz, 2H) 8.19 (d, J=8.59 Hz, 2H)8.33 (s, 1H) 8.63 (s, 1H). MS [M+H] found 449.

Example: 7(S)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylureaand Example: 8(R)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylurea

The racemate of the title compound was prepared by method similar toExample 1. The racemate of the title compound was purified bypreparative HPLC (eluting with a gradient of 25-25% ACN (containing0.035% TFA) in water (containing 0.05% TFA) using a Sunfire Prep 5 μmC18, 75×30 mm column). The racemate was then chirally separated onChiralPak AD-H (5 μm, 20×250 mm, 40% of MeOH:nPrOH (2:1) in liquid CO₂)to give the title compounds. Isomer 1 had a retention time of 0.95minutes on ChiralPak AD-H column (5 μm, 2.1×150 mm, 40% of EtOH(containing 10 mM NH₄OAc) in liquid CO₂). ¹H NMR (400 MHz, METHANOL-d₆)δ ppm 0.42 (m, 2H) 0.55 (m, 2H) 1.17 (t, J=8 Hz, 3H) 1.21 (m, 1H) 1.46(s, 3H) 3.24 (quartet, J=8 Hz, 2H) 3.36 (m, 1H) 3.67 (dt, J=12, 4 Hz 1H)3.74 (d, J=12 Hz, 1H) 3.84 (dd, J=12, 8 Hz, 1H) 3.98 (dd, J=12, 8 Hz,1H) 4.10 (d, J=12 Hz, 1H) 4.13 (m, 1H) 4.30 (dd, J=12, 4 Hz, 1H) 7.46(d, J=8 Hz, 2H) 8.21 (d, J=8 Hz, 2H) 8.21 (s, 1H). MS [M+H] found 437.4.Isomer 2 had a retention time of 2.21 minutes on ChiralPak AD-H column(5 μm, 2.1×150 mm, 40% of EtOH (containing 10 mM NH₄OAc) in liquid CO₂).¹H NMR (400 MHz, METHANOL-d₆) δ ppm 0.42 (m, 2H) 0.55 (m, 2H) 1.17 (t,J=8 Hz, 3H) 1.21 (m, 1H) 1.46 (s, 3H) 3.24 (quartet, J=8 Hz, 2H) 3.36(m, 1H) 3.67 (dt, J=12, 4 Hz 1H) 3.74 (d, J=12 Hz, 1H) 3.84 (dd, J=12, 8Hz, 1H) 3.98 (dd, J=12, 8 Hz, 1H) 4.10 (d, J=12 Hz, 1H) 4.13 (m, 1H)4.30 (dd, J=12, 4 Hz, 1H) 7.46 (d, J=8 Hz, 2H) 8.21 (d, J=8 Hz, 2H) 8.21(s, 1H). MS [M+H] found 437.4.

Example: 9(S)-1-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 10(R)-1-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

To a mixture of2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (3g, 12.47 mmol) in DMSO (10 mL) cooled in an ice water bath was addedsodium tert-butoxide (1.32 g, 13.7 mmol). After 15 minutes stirring, themixture was allowed to warm up to room temperature and stirred for 45minutes. Then (bromomethyl)cyclopropane (1.27 mL, 13 mmol) was addeddropwise in 12 minutes and the resulting mixture stirred at roomtemperature for 15 hours. Water was added and the resulting yellowprecipitate was collected by vacuum filtration and washed repeatedlywith water. The solid was subjected to vacuum for 4 hours to give2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a yellow solid (3.57 g, 97%). MS [M+H] found 295.2.

To2-chloro-5-(cyclopropylmethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(3.57 g, 12.11 mmol) in DMSO (28 mL) was added iodomethane (0.907 mL,14.54 mmol), and the mixture was cooled in an ice-water bath. Thensodium tert-butoxide (1.39 g, 14.54 mmol) was added. After 5 minutesstirring at 0° C., the mixture was allowed to warm up to roomtemperature and stirred for 17 hours. The reaction mixture was cooled inan ice-water bath and more iodomethane (0.378 mL) was added, followed bymore sodium tert-butoxide (582 mg). The mixture was warmed up to roomtemperature and stirred for 55 minutes, then sealed and heated at 50° C.(bath temperature) for 1 hour. The reaction was cooled to roomtemperature and additional iodomethane (3 mL) was added, then sealed andheated at 50° C. (bath temperature) for another 27 minutes then cooledin an ice-water bath and more sodium tert-butoxide (582 mg) was added.The mixture was then warmed up to room temperature and stirred for 75minutes. The reaction mixture was then diluted with water and extractedwith EtOAc. The organic layers were combined and solvent was removed togive a brown solid. The solid was dissolved in dichloromethane andpurified on silica gel eluting with Hexanes-EtOAc (0-50%), to give2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a solid (773 mg, 33%). MS [M+H] found 309.2.

To2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(773 mg, 2.5 mmol) was added1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.908 g, 3.0 mmol), Pd(dppf)Cl₂-dichloromethane, 1,4-dioxane (10 mL)and NaHCO₃ (sat., 5 mL) and the mixture was heated under an air balloon(1 atm) at 100° C. (bath temperature) for 35 minutes and then at 110° C.for 1 hour and 22 minutes. Most of the solvent was evaporated on therotary evaporator to give a residue. The residue was diluted with MeOHand filtered through a microfilter. The solid collected was rinsedrepeatedly with MeOH to give the racemic product as a light grayishsolid (600 mg, desired product). The clear filtrate was purified by HPLC(25-30% of AcCN [containing 0.035% TFA] in water [containing 0.05% TFA],Phenomenex Gemini 5 μm C18, 75×30 mm column) to give an additional batchof the racemic product as a white solid (200 mg). Chiral separation wasperformed on ChiralPak AD-H column (5 μm, 20×150 mm, 45% of MeOH—PrOH[2:1] in liquid CO₂) to give(S)-1-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaas a white solid (225 mg, 20%). The title compound had a retention timeof 1.43 minutes on ChiralPak AD-H column (5 μm, 2.1×150 mm, 40% ofi-PrOH (containing 10 mM NH₄OAc) in liquid CO₂). ¹H NMR (400 MHz,METHANOL-d₆) δ ppm 0.44 (m, 2H) 0.53 (m, 4H) 0.75 (m, 2H) 1.22 (m, 1H)1.47 (s, 3H) 2.60 (m, 1H) 3.38 (m, 1H) 3.67 (dt, J=12, 4 Hz, 1H) 3.75(d, J=12 Hz, 1H) 3.84 (dd, J=12, 8 Hz, 1H) 3.98 (dd, J=12, 8 Hz, 1H)4.10 (d, J=8 Hz, 1H) 4.13 (m, 1H) 4.32 (dd, J=12, 4 Hz, 1H) 7.49 (d, J=8Hz, 2H) 8.21 (s, 1H) 8.21 (d, J=8 Hz, 2H). MS [M+H] found 449.4.

Example: 111-methyl-3-(4-(6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

To a mixture of2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (100mg, 0.416 mmol), K₂CO₃ (115 mg, 0.831 mmol) in DMF (2 mL) at 0° C., wasadded 3-(chloromethyl)-1-methyl-1H-pyrazole (54.3 mg, 0.416 mmol). Themixture was stirred at 0° C. for 30 minutes and then at room temperaturefor overnight. Water was added and the mixture was extracted with EtOAc(2×). The aqueous layer was basified and then extracted with EtOAc. Thecombined organic layers were dried over MgSO₄, filtered and evaporatedin vacuo to give2-chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(104 mg) which was used in the next step without further purification.MS [M+H] Found 335.

2-Chloro-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(100 mg, 0.299 mmol) and iodomethane (0.037 mL, 0.597 mmol) were mixedin DMSO (2 mL) in a sealed scintillation vial. The mixture was frozenthen sodium 2-methylpropan-2-olate (57.4 mg, 0.597 mmol) was added andcovered with a layer of DMSO. The mixture was refrozen then allowed towarm to room temperature and stirred overnight. An additional 1 eq ofiodomethane was added. After 1 hour the reaction was diluted with waterand extracted into EtOAc. The organic layer was dried over magnesiumsulfate, filtered, and evaporated in vacuo to give2-chloro-6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a yellow oil, which was used without further purification. MS [M+H]Found 349.

A mixture of2-chloro-6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(118 mg), PdCl₂(dppf) (43.6 mg),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(124 mg, 0.447 mmol), saturated sodium bicarbonate solution (1.5 mL),and 1,4-dioxane (3 mL) was heated by microwave irradiation at 100° C.for 45 minutes. The reaction mixture was diluted with 2 mL of methanol,filtered then purified by mass-triggered preparative HPLC eluted with20-30% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) ona Phenomenex Gemini 5 μm C18, 75×30 mm column to give the title compound(36 mg) as a pale yellow solid. ¹H NMR (400 MHz, METHANOL-d₄) δ ppm 1.72(s, 3H) 2.80 (s, 3H) 3.57 (m, 1H) 3.70 (m, 1H) 3.85 (s, 3H) 3.89 (d,J=12 Hz, 1H) 4.15 (dd, J=12, 4 Hz, 1H) 4.19 (d, J=12 Hz, 1H) 4.71 (m,1H) 4.95 (d, J=12 Hz, 1H) 5.30 (d, J=12 Hz, 1H) 6.24 (d, J=4 Hz, 1H)7.55 (d, J=4 Hz, 1H) 7.63 (d, J=8 Hz, 2H) 8.07 (d, J=8 Hz, 2H) 8.12 (s,1H). MS [M+H] Found 463.

Example: 121-methyl-3-(4-(6a-methyl-5-((3-methyloxetan-3-yl)methyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 1 using 33-(bromomethyl)-3-methyloxetane as reactant in the alkylation and waspurified by HPLC using mass-triggered preparative HPLC (eluted with25-30% of ACN (containing 0.035% TFA) in water (containing 0.05% TFA) ona Phenomenex Gemini 5 μm C18, 75×30 mm column). The title compound wastaken to the next step without isolation.

Example: 131-(4-(5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

The product of Example 12 was purified by HPLC using mass-triggeredpreparative HPLC (eluted with 25-30% of ACN (containing 0.035% TFA) inwater (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mmcolumn). Oxetane containing fractions were collected and the solventreduced and were repurified by HPLC under the same conditions. Fractionscontaining the title compound were evaporated in vacuo to give a residuewhich was dissolved in methanol for transfer then the solvent removedunder a stream of nitrogen to give the title compound (39 mg). ¹H NMR(400 MHz, METHANOL-d4) δ ppm 0.92 (s, 3H) 1.73 (s, 3H) 2.80 (s, 3H)3.38-3.4 (m, 4H) 3.57 (m, 1H) 3.69 (m, 1H) 3.83 (m 2H) 4.13-4.18 (m, 3H)4.74 (m, 1H) 7.64 (d, J=8 Hz, 2H) 8.10 (d, J=8 Hz, 2H) 8.63 (s, 1H). MS[M+H] Found 471.5.

Example: 141-(4-(5,6a-dimethyl-4-morpholino-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

2,4,6-Trichloro-5-nitropyrimidine (1 g, 4.38 mmol) was suspended in EtOH(10 mL). Raney-Nickel®2800 in water (1.285 g, 21.89 mmol) was added andthe vessel was purged with hydrogen gas and stirred at atmosphericpressure and room temperature overnight. After filtration throughCelite® the filtrate was evaporated to give 1.3 g of crude2,4,6-trichloropyrimidin-5-amine. MS [M+H] Found 200.

A round-bottom flask was charged with 2,4,6-trichloropyrimidin-5-amine(982 mg, 4.95 mmol), morpholine-3-carboxylic acid (649 mg, 4.95 mmol)and triethylamine (2.78 mL, 19.79 mmol) in ethanol (20 mL). The mixturewas heated at 75° C. for 3 days then diluted with water and extractedwith EtOAc. The organic layer was dried over magnesium sulfate, filteredand dried in vacuo to give 500 mg of crude2,4-dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-onewhich was used without further purification. MS [M+H] Found 275.

2,4-Dichloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(500 mg, 1.818 mmol) and iodomethane (1.134 mL, 18.18 mmol) were mixedin DMSO (3 mL). 2-Methylpropan-2-olate (699 mg, 7.27 mmol) was added andthe suspension was stirred overnight at room temperature. Ten moreequivalents of iodomethane were added and the solution was heated at 50°C. for about 18 hours. The reaction was purified by mass-triggeredpreparative HPLC 20-60% of ACN (containing 0.035% TFA) in water(containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mmcolumn)) to give 20 mg of2,4-dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a tan solid. MS [M+H] Found 289.

2,4-Dichloro-5-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(20 mg, 0.069 mmol) and iodomethane (9.82 mg, 0.069 mmol) were stirredin DMSO (2 mL). The mixture was frozen then 2-methylpropan-2-olate(19.94 mg, 0.208 mmol) was added as a solid followed by a layer of DMSO.The mixture was refrozen then allowed to warm up to room temperature andstirred for 1 hour. The reaction was diluted with water and extractedtwice with EtOAc, the organic layers combined, dried over magnesiumsulfate, filtered and evaporated in vacuo to give 20 mg (95%) of2,4-dichloro-5,6a-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a white solid. MS [M+H] Found 303.

2,4-Dichloro-5,6a-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(20 mg, 0.066 mmol), triethylamine (18.44 μL, 0.132 mmol) and morpholine(5.75 μL, 0.066 mmol) were mixed in dichloromethane at room temperatureand stirred over the weekend at 50° C. The solvent was removed in vacuoto give crude2-chloro-5,6a-dimethyl-4-morpholino-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one.MS [M+H] Found 354.

2-Chloro-5,6a-dimethyl-4-morpholino-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(23 mg, 0.065 mmol),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(21.54 mg, 0.078 mmol), PdCl₂(dppf) (9.51 mg, 0.013 mmol) and sodiumbicarbonate (1.5 mL, sat.) were mixed in 1,4-dioxane (3 mL). Thesuspension was heated by microwave irradiation at 100° C. for 30minutes. After filtration, the solution was purified by mass-triggeredpreparative HPLC eluted with 20-25% of ACN (containing 0.035% TFA) inwater (containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mmcolumn) to give the title compound (5.3 mg 17% yield) as a pale yellowsolid. ¹H NMR (400 MHz, MeOD) δ ppm 1.57 (s, 3H) 2.70 (s, 3H) 2.80 (s,3H) 3.34 (m, 1H) 3.64 (m, 1H) 3.72-3.86 (m, 9H) 4.10 (m, 2H) 4.25 (m,1H) 7.51 (d, J=8 Hz, 2H) 7.62 (d, J=8 Hz, 2H). MS [M+H] Found 468.

Example: 151-(4-(5-isopropyl-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

In a 100 mL flask containing 2,4-dichloropyrimidin-5-amine (1.0 g, 6.10mmol) in 16.5 mL of dichloromethane was added acetone (1.062 g, 18.29mmol). The solution was cooled to 0° C. then a solution of titaniumtetrachloride (0.740 mL, 6.71 mmol) in 10 mL of dichloromethane wasadded slowly. The mixture was stirred at room temperature for 2 hours.Sodium cyanoborohydride (1.150 g, 18.29 mmol) was added in 4 equalportions over 10 minutes and the reaction was stirred at roomtemperature for 2 hours. The reaction was quenched with water (150 mL)and extracted with t-BuOMe twice. The organic layers were combined,dried with Na₂SO₄, filtered and concentrated in vacuo. The residue wasdissolved in methanol and adsorbed onto silica. The residue was purifiedon silica gel using 0-10% methanol in dichloromethane as eluent.Relevant fractions were evaporated in vacuo to give 940 mg (74%) of2,4-dichloro-N-isopropylpyrimidin-5-amine as a pale yellow oil. MS [M+H]Found 206.

A round-bottom flask was charged with2,4-dichloro-N-isopropylpyrimidin-5-amine (940 mg, 4.56 mmol),morpholine-3-carboxylic acid hydrochloride (994 mg, 5.93 mmol), DIPEA(3.19 mL, 18.25 mmol) and DMSO (8 mL). The flask was heated overnight at100° C. The solution was diluted with water and refrigerated for 2hours. The aqueous solution was extracted twice with EtOAc. The organiclayers were combined, dried over magnesium sulfate, filtered, andevaporated in vacuo to give2-chloro-5-isopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a brown solid (1.2 g). MS [M+H] Found 283.

2-Chloro-5-isopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(1.20 g, 4.24 mmol) and iodomethane (1.324 mL, 21.22 mmol) were mixed inDMSO. The mixture was frozen, 2-methylpropan-2-olate (1.224 g, 12.73mmol) was added, covered by a layer of DMSO and refrozen. The mixturewas allowed to room temperature and stirred overnight. Another 1 eq of2-methylpropan-2-olate and iodomethane was added and the mixture stirredovernight at 30° C. The solution was diluted with water and extractedwith EtOAc twice. The organic layers were combined, dried over magnesiumsulfate, filtered, and evaporated in vacuo. The residue was absorbedonto silica and purified by column chromatography using 10-60% EtOAc inhexanes then 5% methanol in dichloromethane as eluent. Relevantfractions were evaporated in vacuo to give 98 mg (8%)2-chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one.MS [M+H] Found 297.

2-Chloro-5-isopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(98 mg, 0.330 mmol) was mixed with PdCl₂(dppf) (48.3 mg),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(100 mg, 0.363 mmol) and saturated sodium bicarbonate solution (2 mL,sat.) in 1,4-dioxane (4 mL). The suspension was heated by microwaveirradiation at 100° C. for 30 minutes. The suspension was filtered, thesolids washed with methanol then DMSO and the filtrate evaporated invacuo. The resulting solid was purified by mass-triggered preparativeHPLC eluted with 20-35% of ACN (containing 0.035% TFA) in water(containing 0.05% TFA) on a Phenomenex Gemini 5 μm C18, 75×30 mm column)to give the title compound (30 mg 22% yield) as a pale yellow solid. ¹HNMR (400 MHz, METHANOL-d₄) δ ppm 1.55 (m, 6H) 1.62 (s, 3H) 2.80 (s, 3H)3.50 (td, J=12, 4 Hz, 1H) 3.68 (td, J=12, 4 Hz, 1H) 3.79 (d, J=12 Hz,1H) 4.14 (m, 1H) 4.62 (dd, J=12, 4 Hz, 1H) 4.66 (m, 1H) 7.62 (d, J=8 Hz,2H) 8.10 (d, J=8 Hz, 2H) 8.13 (s, 1H). MS [M+H] Found 411.

Preparation 1:2-chloro-5-(cyclopropylmethyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one

Morpholine-3-carboxylic acid (10 g, 76 mmol) was dissolved in water (50ml) and cooled to 5° C. A solution of 50% sodium hydroxide (6.10 g, 76mmol) was added and the reaction mixture was cooled back to 5° C. Anadditional portion of 50% sodium hydroxide (7.93 g, 99 mmol) was thendiluted to 22 mL with water and added to an addition funnel. Benzylchloroformate (65.3 ml, 458 mmol) was added to a separate additionfunnel and the two reagents were simultaneously added dropwise overabout 30 minutes while maintaining the reaction temperature below 10° C.The pH of the mixture was about 6 when the addition was completed.Additional 50% NaOH (1.13 g, 14.3 mmol) was added to adjust pH to 9. Thereaction was stirred at 10-15° C. for 2 hours. The reaction mixture wasextracted with hexanes (2×30 ml) to remove excess benzyl chloroformate.EtOAc (50 ml) was added into the aqueous phase. The mixture wasacidified to pH of about 0 with concentrated HCl (10 g). The organicphase was separated and the aqueous phase was extracted with EtOAc(3×100 ml). The combined organic solution was concentrated to afford anoil. The product was further dried under high vacuum overnight to afford21.2 g of crude 4-(benzyloxycarbonyl)morpholine-3-carboxylic acid whichwas used in the next step without further purification. [M−H] calculatedfor C₁₃H₁₅NO₅, 264. found, 264.

4-(Benzyloxycarbonyl)morpholine-3-carboxylic acid (crude material, 21.2g, about 75 mmol) was dissolved in methanol (250 ml). Sulfuric acid(12.01 ml, 225 mmol) was added slowly with vigorous stirring. Anexotherm was noticed and the temperature rose to 34° C. after theaddition. Once the addition was complete, reaction solution was heatedto 50° C. for 18 hours. The reaction mixture was cooled to roomtemperature and concentrated to remove most of the methanol. EtOAc (500ml) was added and the organic solution was washed with water (150 ml),saturated sodium bicarbonate solution (100 ml) and water (150 ml). Theorganic solution was then concentrated to give a residue which waspurified by silica gel column (330 g silica gel, hexanes/EtOAc 5:1) toafford 15.9 gram of 4-benzyl 3-methyl morpholine-3,4-dicarboxylate asclear oil. ¹H NMR (400 MHz, CDCl₃) δ=3.28-3.57 (m, 2H), 3.67 (m, 1H),3.57-3.96 (m, 5H), 4.4 (dd, 1H), 4.61 (dd, 1H), 5.19 (m, 2H), 7.32-7.4(m, 5H)

4-Benzyl 3-methyl morpholine-3,4-dicarboxylate (13.98 g, 50.1 mmol) andmethyl iodide (5.70 ml, 91 mmol) was dissolved in THF (100 ml). Thesolution was cooled to −70° C. A solution of NaHMDS in THF (1 M, 91 ml,91 mmol) was added via syringe over 2 minutes. The reaction solution wasstirred for 5 hours at −40 to −70° C. and then was quenched with MeOH (5ml) and HOAc (3.5 g). The reaction mixture was concentrated. The residuewas then partitioned between EtOAc (400 ml) and water (150 ml). Theorganic phase was separated. The aqueous phase (pH about 7) wasextracted with EtOAc (100 ml). The combined organic phases were washedwith water (100 ml). The organic solution was then concentrated to givean oil. The residue was purified by silica gel column (220 g silica gel,Hexane/EtOAc 5:1) to afford 11.6 g of 4-benzyl 3-methyl3-methylmorpholine-3,4-dicarboxylate as an oil (79% yield). ¹H NMR (400MHz, CDCl₃) δ=1.58 (s, 3H), 3.23-3.78 (m, 9H), 4.99 (m, 2H), 7.17-7.27(m, 5H)

4-Benzyl 3-methyl 3-methylmorpholine-3,4-dicarboxylate (7.751 g, 26.4mmol) was dissolved in EtOH (100 ml). 10% Pd/C (1.406 g, 1.321 mmol) wasthen added. The flask was purged with nitrogen and evacuated beforehydrogen was introduced. The mixture was then hydrogenated under 1atmosphere of hydrogen for 16 hours. The Pd/C was removed by filteringthrough a Celite® pad. The filtrate was concentrated to afford theproduct as an oil. MS [M+H] calculated for C₇H₁₃NO₃, 160. found, 160.

Methyl 3-methylmorpholine-3-carboxylate (4.21 g, 26.4 mmol) wasdissolved in THF (60 ml) to form a clear solution.2,4-Dichloro-5-nitropyrimidine (5.13 g, 26.4 mmol) was added and thesolution was cooled to −10° C. Diisopropylethylamine (6.93 ml, 39.7mmol) was added while the temperature was maintained at −8 to −10° C.The reaction was stirred for 4 hours at 0° C. and for 16 hours at roomtemperature. The solvent was removed under reduced pressure. EtOAc (120ml) was added and the mixture was washed with water (3×30 ml). Theorganic solution was concentrated to afford 8.4 g of crude methyl4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate asan oil. The crude material was used in the next step without furtherpurification. MS [M+H] calculated for C₁₁H₁₃ClN₄O₅, 317. found, 317.

Methyl4-(2-chloro-5-nitropyrimidin-4-yl)-3-methylmorpholine-3-carboxylate(crude material, 8.4 g, about 20 mmol) and vanadyl actylacetonate (0.7g, 2.64 mmol) were mixed in THF (80 ml). The reaction mixture washydrogenated under one atmosphere of hydrogen at 35° C. for 18 hours.The starting material was consumed. The reaction mixture was cooled toroom temperature. MeOH (10 ml) was added to reaction mixture and stirredfor 10 minutes. The mixture was filtered through a Celite® pad. TheCelite® pad was washed with mixture of THF (60 ml) and MeOH (10 ml)twice and then a mixture of dichloromethane (80 ml) and methanol (20 ml)three times. The filtrate was combined with washes and concentrated toabout 30 ml at which point a solid had precipitated out. EtOAc (40 ml)was added and the mixture was stirred for 10 minutes. The solid wascollected by filtration, washed with EtOAc (50 ml) to afford 2.54 g of2-chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one.¹H NMR (400 MHz, CDCl₃) δ=1.44 (s, 3H), 3.23 (m, 1H), 3.53 (m, 1H), 3.69(d, 1H), 3.88-3.99 (m, 3H), 7.67 (s, 1H), 10.98 (s, 1H)

2-Chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.846 g, 3.32 mmol) and (bromomethyl)cyclopropane (0.672 g, 4.98 mmol)were mixed in DMSO (5 ml). Potassium carbonate (0.918 g, 6.64 mmol) wasadded. The mixture was stirred for 30 minutes at room temperature andthen for 2 hours at 35° C. EtOAc (40 ml) was added followed by additionof water (30 ml). Aqueous phase was separated and extracted with EtOAc(2×30 ml). The combined organic phase was washed with water (2×20 ml).The organic solution was concentrated to near dryness at which point asolid had precipitated out. EtOAc (5 ml) and hexanes (20 ml) were addedand the mixture was stirred for 20 minutes. The solid was collected byfiltration to afford 1.35 g product as a white solid. Concentration andcrystallization of mother liquor afforded another 0.28 g of compound assecond crop. ¹H NMR (400 MHz, CDCl₃) δ=0.34 (m, 2H), 0.46 (m, 2H), 1.13(m, 1H), 1.39 (s, 3H), 3.21 (m, 1H), 3.55 (m, 1H), 3.66 (d, 1H), 3.77(m, 1H), 3.85-4.02 (m, 4H), 8.20 (s, 1H)

Preparation 2: methyl 3-methylmorpholine-3-carboxylate

Combine 4-benzyl-5-(hydroxymethyl)-5-methylmorpholin-3-one (11.75 g,0.05 mol) ethyl acetate (75 ml), and KBr in water (0.5 M, 10 ml),followed by addition of 2,2,6,6-tetramethylpiperidine-1-oxyl (0.16 g, 1mmol). Add solution of 12% NaClO in water (39 g, 62.5 mmol) dropwise tothe mixture over 30 minutes at 5° C. at pH of 8.0-10.0. After 30minutes, adjust the pH to 5.0 by addition of 35% hydrochloric acid,followed by addition of 25% NaClO2 in water (22.7 g, 62.5 mmol) over 30minutes. Stirring continues for 3 hours at ambient temperature. Recoverthe product by extraction with ethyl acetate, washed with brine, to give4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid.

Dissolve 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylic acid (1 eq) inMeOH (10 volumes) and stir. Add sulfuric acid (3 eq) dropwise. Heat at50° C. for 24 hours. Cool to room temperature and concentrate. Add EtOAc(25 volumes) wash with water (7 volumes), followed by saturated aqueousNaHCO₃ (5 volumes), and then water (7 volumes). Dry the EtOAc layer andconcentrated to give methyl4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate.

Dissolve methyl 4-benzyl-3-methyl-5-oxomorpholine-3-carboxylate in THF(10 volumes) and cool to 0° C. Add borane dimethylsulfide complex (1.5eq) and allow to warm to room temperature. Add water (5 volumes)followed by EtOAc (10 volumes). Separate the organic layer, wash withsaturated aqueous NaCl, dry over sodium sulfate, filtered, andconcentrate to give methyl 4-benzyl-3-methylmorpholine-3-carboxylate.

Dissolve methyl 4-benzyl-3-methylmorpholine-3-carboxylate in EtOH (10volumes) and add 10% Pd/C (0.1 eq.). Hydrogenate for 16 hours, filterthrough Celite®, and concentrate to give the title compound.

Example: 161-(4-(5-(cyclobutylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by silica gel column chromatography(eluting with 2 to 5% gradient of MeOH in Chloroform) to afford thetitle compound as a off white solid (15 mg, 17% yield). ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.27 (s, 3H) 1.61-1.79 (m, 4H) 1.80-1.96 (m, 2H)2.51-2.67 (m, 4H) 3.10-3.19 (m, 1H) 3.45-3.64 (m, 2H) 3.83-4.05 (m, 4H)4.11 (m, 1H) 5.92-6.08 (m, 1H) 7.35-7.47 (d, J=8.0 Hz, 2H) 8.05-8.14 (d,J=8.0 Hz, 2 hours) 8.18 (s, 1H) 8.63 (s, 1H). MS [M+H] found 437.

Example: 171-(4-(5-cyclopropyl-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

A round-bottomed flask equipped with a magnetic stirrer was added2,4-dichloro-5-fluoropyrimidine (0.835 g, 5 mmol), DMSO (1 ml),morpholine-3-carboxylic acid (0.656 g, 5.00 mmol) and DIPEA (3.49 ml,20.00 mmol). The reaction was stirred at 80° C. for 10 minutes thencooled to ambient temperature, HATU (2.85 g, 7.50 mmol) was addedfollowed by cyclopropanamine (0.526 ml, 7.50 mmol) and the reactionmixture was again heated at 80° C. for 2 hours. Upon completion thereaction was suspended in water and filtered. The collected solid waswashed successively with water, small amount of ethanol and diethylether. The solid was dried in vacuo for 16 hours to afford4-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopropylmorpholine-3-carboxamide(0.325 g, 1.081 mmol, 21.62% yield) as a white solid.

A scintillation vial equipped with a magnetic stirrer was added4-(2-chloro-5-fluoropyrimidin-4-yl)-N-cyclopropylmorpholine-3-carboxamide(325 mg, 1.081 mmol), DMF (5 ml), Cs₂CO₃ (528 mg, 1.621 mmol). Thereaction was stirred at 60° C. for 16 hours. The reaction solution waspoured into water, extracted with ethyl acetate three times and thecombined organic layers washed with sat. NaCl. The organic layers weredried with Na₂SO₄, filtered and dried in-vacuo to give a yellow solid.The crude material was washed with diethyl ether and filtered to afford2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(121 mg, 0.431 mmol, 39.9% yield) as a white solid. MS [M+H] found 281.

A round-bottomed flask equipped with a magnetic stirrer was added2-chloro-5-cyclopropyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(121 mg, 0.431 mmol), DMSO (2 ml), and iodomethane (0.032 ml, 0.517mmol). The mixture was cooled to 0° C. and added sodium2-methylpropan-2-olate (49.7 mg, 0.517 mmol) and allowed to stir at 20°C. for 16 hours. The reaction solution was suspended in water, and theprecipitate filtered. The collected solid was washed successively withsmall amount of ethanol and diethyl ether. The solid was collected anddried in-vacuo to afford2-chloro-5-cyclopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(100 mg, 0.339 mmol, 79% yield) as a tan solid. MS [M+H] found 295.

A microwave vial equipped with a magnetic stirrer was added2-chloro-5-cyclopropyl-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(100 mg, 0.339 mmol), 1,4-dioxane (2 ml),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(141 mg, 0.509 mmol), NaHCO₃ (585 μl), followed by PdCl₂(dppf) (12.41mg, 0.017 mmol). The reaction was irradiated in the microwave at 100° C.for 40 min. Upon completion the reaction solution was poured into waterand the precipitate filtered. The collected solid was successivelywashed with water and small amount of ethanol and dried in-vacuo toobtain a solid. This solid was further purified by silica gelchromatography (2 to 5% gradient of MeOH in chloroform). The fractionswere collected and concentrated in-vacuo to afford the title compound(27 mg, 0.066 mmol, 19.48% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₄, D₂O) δ ppm 0.55 (m, 1H) 0.78-0.92 (m, 1H) 1.01-1.11 (m, 1H)1.12-1.24 (m, 2H) 1.45 (s, 3H) 2.65 (s, 3H) 2.78 (s, 1H) 3.26-3.40 (m,1H) 3.55 (m, 1H) 3.70 (d, J=11.6 Hz, 1H) 3.93 (d, J=11.4 Hz, 1H) 4.02(m, 1H) 4.30-4.39 (m, 1H) 7.54 (d, J=8.8 Hz, 2H) 8.08-8.16 (d, J=8.8 Hz,2H) 8.20 (s, 1H). MS [M+H] found 409.

Example: 181-(4-((6aS,7S)-5-(cyclopropylmethyl)-6a,7-dimethyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

To (2R,3S)-2-amino-3-hydroxybutanoic acid (14.7 g, 123 mol) in NaOH(50%, 70 mL) was added benzaldehyde (14 mL, 123 mmol). The white slurrywas stirred at room temperature for 18 h and then cooled to 0° C. NaBH₄(675 mg, 17.9 mmol) was added in two portions over 10 minutes Coolingbath was removed and the thick slurry was stirred at room temperaturefor 40 minutes and addition NaBH₄ (659 mg, 17.4 mmol) was added andstirred at 0° C. for 40 minutes Benzaldehyde (10 mL, 99 mmol) was added,cooled to 0° C. and additional NaBH₄ (700 mg, 18.5 mmol) was added.After 5 minutes warmed up to room temperature and stirred for 2 hour.The reaction mixture was acidified with HCl (conc.) to pH of (about 3)and then filtered precipitate, washed with cold water and dried to give(2R,3S)-2-(benzylamino)-3-hydroxybutanoic acid (3.4 g, 13.2%) of whitesolid. MS [M+H] found 210.

A round-bottomed flask equipped with a magnetic stirrer was added(2R,3S)-2-(benzylamino)-3-hydroxybutanoic acid, HCl (3.4 g, 13.84 mmol),Water (20 ml), sodium hydroxide (1.937 g, 48.4 mmol) and cooled to 0° C.2-Chloroacetyl chloride (2.201 ml, 27.7 mmol) was added dropwise. Thereaction was warmed to 20° C. over 2 hour. The reaction solution wasneutralized with 6 N HCl to pH about 2. The reaction solution wasextracted with ethyl acetate, and washed with saturated NaCl. Theorganic layers were collected, dried over Na₂SO₄, filtered, concentratedin-vacuo to afford(2S,3R)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid (3.04 g,88%) a white solid. MS [M+H] found 250.

A round-bottomed flask equipped with a magnetic stirrer was added(2S,3R)-4-benzyl-2-methyl-5-oxomorpholine-3-carboxylic acid (1 g, 4.01mmol), EtOH (20 ml), thionyl chloride (1.155 ml, 16.05 mmol). Thereaction was stirred at 20° C. for 72 hours. Concentrate in vacuo toafford a crude oil. The oil was purified by silica gel columnchromatography (eluting with 20% EtOAc in Hexanes using the MoritexSI-60 size 60—half column). The resultant fractions were collected andconcentrated in-vacuo to afford (2S,3R)-ethyl4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (683 mg, 2.46 mmol,61.4% yield) as a white solid. MS [M+H] found 278.

To (2S,3R)-ethyl 4-benzyl-2-methyl-5-oxomorpholine-3-carboxylate (683mg, 2.463 mmol) in THF (6 ml), BH₃SMe₂ (0.350 ml, 3.69 mmol) at 0° C.The reaction was stirred at 20° C. for 16 h. The reaction solution wasquenched with water at 0° C. The layers were separated and the aqueouslayer extracted with ethyl acetate. The combined organic layer washedwith saturated NaCl. The organic was collected, dried with Na₂SO₄,filtered and concentrated in-vacuo to give a crude oil. The oil waspurified by silica gel column chromatography (eluting with 10-20%gradient of EtOAc in hexanes using a Moritex SI-60 size 20 column). Theresultant fractions were collected and concentrated in-vacuo to afford(2S,3R)-ethyl 4-benzyl-2-methylmorpholine-3-carboxylate (683 mg, 2.59mmol, 105% yield (contained residual solvent)) as a colorless oil. MS[M+H] found 264.

(2S,3R)-Ethyl 4-benzyl-2-methylmorpholine-3-carboxylate (648 mg, 2.461mmol), ethanol (5 ml), and Pd(OH)₂ (34.6 mg, 0.246 mmol) were combinedin a round-bottomed flask. The mixture was vigorously stirred and purgedof air using house vacuum and recharged with H₂ (three times). Thereaction was stirred at 20° C. for 16 h. Transferred to a Parr® shakerand pressurized to 50 psi (345 kPa) of H₂ for and shaken for 2 hours.The suspension was filtered over a pad of Celite® and washed withethanol (5 ml). The filtrate was concentrated in vacuo to afford(2S,3R)-ethyl 2-methylmorpholine-3-carboxylate (386 mg, 2.229 mmol, 91%yield) as yellow crystal upon standing.

A scintillation vial equipped with a magnetic stirrer was added(2S,3R)-ethyl 2-methylmorpholine-3-carboxylate (383 mg, 2.211 mmol), DMF(3 ml), 2,4-dichloropyrimidin-5-amine (363 mg, 2.211 mmol), followed byDIEA (0.386 ml, 2.211 mmol). The reaction was stirred at 80° C. for 16hours. NaOH (2 mL, 2.5N) was added and continued heating at 110° C. for2 hours. After cooling to room temperature Boc₂O (2 eq.) was added andstirred for 16 hours. The reaction was acidified with HCl (6N) to pH ofabout 2. The reaction mixture was poured into ethyl acetate and washedsuccessively with water, brine, then dried over Na₂SO₄, and concentratedin vacuo to give a crude oil. Crystals formed after standing for 16hours. The crystals were filtered and washed with ether to afforded(6aR,7S)-2-chloro-7-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(128 mg, 0.503 mmol, 22.73% yield) as a brown solid. The mother liquorwas treated with TFA to afforded a crude(2S,3R)-2-methylmorpholine-3-carboxylic acid, TFA (145 mg, 0.559 mmol,25.3% yield) which was combined with 2,4-dichloropyrimidin-5-amine (164mg, 1 mmol) in DMF (1 ml) and DIEA (0.524 ml, 3.00 mmol). The reactionwas heated at 80° C. for 16 hours. The reaction solution was poured intoethyl acetate and successively washed with water and brine. The organiclayer was dried over Na₂SO₄, concentrated in-vacuo to give a brown oil.The oily residue was allowed to stand for 16 hour to give a solid whichwas filtered and rinsed with ether to afford(6aR,7S)-2-chloro-7-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(77 mg, 0.302 mmol, 30.2% yield). MS [M+H] found 255.

To(6aR,7S)-2-chloro-7-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.077 g, 0.302 mmol) in DMSO (1 ml) was added sodium tert-butoxide(0.035 g, 0.363 mmol) and stirred at 0° C. for 10 minutes(bromomethyl)cyclopropane (0.034 ml, 0.333 mmol) was added in DMSO (100μL) and the reaction was stirred at 25° C. for 16 h. Additional(bromomethyl)cyclopropane (0.034 ml, 0.333 mmol) was added and warmed to60° C. for 2 hours. The reaction solution was poured into water,extracted with ethyl acetate and washed with brine. The organic layerwas dried over Na₂SO₄, filtered, concentrated in-vacuo to give a cruderesidue (93 mg, 100%). The residue was used in the next step withoutfurther purification. MS [M+H] found 309.

To(6aR,7S)-2-chloro-5-(cyclopropylmethyl)-7-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.093 g, 0.301 mmol) in DMSO (1 ml) and iodomethane (0.038 ml, 0.602mmol) at 0° C. was added sodium tert-butoxide (0.043 g, 0.452 mmol). Thereaction was allowed to warm to 25° C. and stirred for 2 hours. Thereaction solution was poured into water, extracted with ethyl acetateand washed with brine. The organic layer was dried over Na₂SO₄,filtered, and concentrated in-vacuo to give a crude residue (98 mg,100%). The residue was used in the next step without furtherpurification. MS [M+H] found 323.

A microwave vial equipped with a magnetic stirrer was added crude(6aS,7S)-2-chloro-5-(cyclopropylmethyl)-6a,7-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(98 mg, 0.304 mmol), 1,4-dioxane (1.5 ml),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(126 mg, 0.455 mmol), saturated NaHCO3 (0.500 mL), and PdCl₂(dppf)(11.11 mg, 0.015 mmol). The reaction was irradiated in the microwave at100° C. for 40 minutes. The reaction solution was poured into saturatedNaCl and extracted with ethyl acetate three times. The organic layerswere collected, dried over Na₂SO₄, filtered and concentrated in-vacuo togive a brown residue. The residue was purified by preparative HPLC(eluting with 20-30% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column to afford thetitle compound (6.8 mg, 0.016 mmol, 5.13% yield) as a light brown solid.¹H NMR (400 MHz, METHANOL-d₄) δ ppm 0.46 (m, 2H) 0.60 (m, 2H) 1.20-1.25(m, 1H) 1.41 (d, J=6.6 Hz, 3H) 1.92 (s, 3H) 2.81 (s, 3H) 3.53-3.67 (m,1H) 3.79-3.87 (m, 1H) 3.91 (d, J=7.0 Hz, 2H) 3.99-4.11 (m, 1H) 4.27 (d,J=6.6 Hz, 1H) 4.87-5.00 (m, 1H) 7.65 (d, J=8.8 Hz, 2H) 7.97 (s, 1H) 8.11(d, J=8.8 Hz, 2H). MS [M+H] found 437.

Example: 191-(4-((6aR,9R)-5-(cyclopropylmethyl)-6a,9-dimethyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

To a 100 mL flask was added 1-benzyl 2-methylaziridine-1,2-dicarboxylate (1 g, 4.25 mmol), dichloromethane (12 mL),(R)-1-Chloro-2-propanol (0.76 mL, 8.50 mmol), and boron trifluoridediethyl etherate (0.05 mL, 0.398 mmol). The mixture was stirred at roomtemperature for 15 minutes Solvent was removed in vacuo and the residuepurified on silica gel eluting with Hexanes-EtOAc (0-50%) to give(R)-methyl2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg,41%). MS [M+H] found 330.2.

To a solution of (R)-methyl2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoate (583 mg,1.77 mmol) in THF—H₂O (8 mL-4 mL) was added lithium hydroxidemonohydrate (223 mg, 5.30 mmol). The mixture was stirred at roomtemperature for 25 minutes THF was removed in vacuo and the mixtureextracted with EtOAc and dried over Na₂SO₄. Solvent was removed to givecrude (R)-2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoicacid as an oil. MS [M+H] found 316.2.

To a solution of(R)-2-(benzyloxycarbonylamino)-3-(1-chloropropan-2-yloxy)propanoic acidin MeOH (10 mL) was added Pd on Carbon (10 wt %, catalytic amount). Themixture was stirred under H₂ (1 atm) for 2.5 hours and filtered througha plug of Celite® and rinsed with MeOH. Solvent was removed to give(R)-2-amino-3-(1-chloropropan-2-yloxy)propanoic acid as an off-whitesolid (308 mg, 96%). MS [M+H] found 182.1.

To solution of (R)-2-amino-3-(1-chloropropan-2-yloxy)propanoic acid (298mg, 1.64 mmol) in MeOH (10 mL) was added Et₃N (0.461 mL, 3.28 mmol). Themixture was equipped with a condenser and refluxed at 80° C. (bathtemperature) for 16 hours. More MeOH (10 mL) was added, followed by Et₃N(0.922 mL, 6.56 mmol). The flask was sealed with a rubber septum andheated at 100° C. (bath temperature) for 5 hours. Then2,4-dichloropyrimidin-5-amine (296 mg, 1.80 mmol) was added, followed bymore Et₃N (0.922 mL, 6.56 mmol). After 30 minutes at room temperature,the flask was sealed with a rubber septum and heated at 100° C. (bathtemperature) for 15 hours. Solvent was removed and the residue loaded onsilica gel and purified by column chromatography eluting withHexanes-EtOAc (20-70%). The desired product(R)-2-chloro-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-onewas obtained as a solid (173 mg, containing some impurities). MS [M+H]found 255.1.

To a solution of(R)-2-chloro-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(103 mg, 0.404 mmol) in DMF (2.5 mL) at 0° C. was added sodium hydride(21 mg, 0.526 mmol, 60% in oil). After 35 minutes at 0° C.,(bromomethyl)cyclopropane (0.051 mL, 0.526 mmol) was added. The mixturewas stirred at 0° C. for 30 minutes, then at room temperature for 45minutes and then sealed and heated at 90° C. (bath temperature) for 2hours. More (bromomethyl)cyclopropane (0.250 mL) was added and heated at90° C. for another 24 hours. The mixture was cooled to room temperature,and more sodium hydride (excess) was added followed by(bromomethyl)cyclopropane (0.1 mL). Heating was continued at 90° C. foranother 6 hours. Then the mixture was diluted with EtOAc and water,extracted with EtOAc (3×), and dried over Na₂SO₄. Solvent was removed invacuo to give crude(R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a brown oil (124 mg). MS [M+H] found 309.2.

To(R)-2-chloro-5-(cyclopropylmethyl)-9-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(124 mg, crude) was added iodomethane (0.25 mL, 4 mmol) and DMSO (2 mL).The mixture was cooled to 0° C. and then −78° C. and sodium2-methylpropan-2-olate (0.154 g, 1.6 mmol) was added, followed by moreDMSO (0.7 mL). The cooling bath was removed and the mixture was stirredat room temperature for 14 hours and then diluted with EtOAc and water,extracted with EtOAc and dried over Na₂SO₄. Solvent was removed to givecrude(R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one.MS [M+H] found 323.3.

To a microwave vial containing(R)-2-chloro-5-(cyclopropylmethyl)-6a,9-dimethyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(about 0.4 mmol) was added1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.133 g, 0.48 mmol), Pd(dppf)Cl₂-dichloromethane, 1,4-dioxane (1.2 mL)and NaHCO3 (sat., 0.6 mL). It was heated in a microwave at 100° C. for 1hour 45 minutes and then conventionally at 100° C. (bath temperature)for 3 hours. The mixture was diluted with MeOH, passed through amicrofilter. The filtrate was purified on the HPLC (40-60% of AcCN inwater containing 10 mM NH₄HCO₃, Phenomenex Gemini 5 μm C18, 75×30 mmcolumn) to give a mixture containing the title product, which wasfurther purified and resolved on a ChiralPak AD-H (5 μm, 10×250 mm,25-25% of MeOH in liquid CO₂) to give the title compound as a whitesolid (2.1 mg) and having a retention time of 5.20 minutes on ChiralPakAD-H column (5 μm, 2.1×150 mm, 26% of MeOH in liquid CO₂). ¹H NMR (400MHz, METHANOL-d₆) δ ppm 0.4-0.56 (m, 4H) 1.22 (m, 1H) 1.34 (d, J=4 Hz,3H) 1.44 (s, 3H) 2.79 (s, 3H) 2.95 (dd, J=16, 12 Hz, 1H) 3.73 (m, 1H)3.82 (m, 2H) 3.95 (m, 1H) 4.12 (d, J=12 Hz, 1H) 4.35 (dd, J=12, 4 Hz,1H) 7.46 (d, J=8 Hz, 2H) 8.19 m (s, 1H) 8.20 (d, J=8 Hz, 2H). MS [M+H]found 437.4.

Example: 202-methyl-2-(6a-methyl-2-(4-(3-methylureido)phenyl)-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)propanoicacid TFA salt

To a mixture of2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (952mg, 3.96 mmol), ethyl 2-iodoacetate (1.27 g, 5.93 mmol) in DMF (14 ml)was added K₂CO₃ (1.64 g, 11.9 mmol) and the reaction mixture was stirredat room temperature for 1 hour. The reaction mixture was concentrated invacuo to remove DMF. The residue was partitioned between EtOAc andwater. The phases were separated and the aqueous phase was extractedwith EtOAc. The combined organic phases were washed successively withwater and saturated aqueous NaCl, then dried over Na₂SO₄, filtered andconcentrated in vacuo to give a crude solid. The residual solid waspurified by silica gel chromatography (hexane/ethyl acetate, 19:1 to1:1) to afford a pale yellow solid. The solid was triturated withhexane/ethyl acetate (4:1), collected by filtration, rinsed withhexane/ethyl acetate (5:1) and dried to afford ethyl2-(2-chloro-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate(953 mg, 2.92 mmol, 74% yield) as a white solid. MS [M+H] found 327.

To a mixture of ethyl2-(2-chloro-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)acetate(440 mg, 1.35 mmol) and iodomethane (1.26 ml, 20.2 mmol) in DMSO (10 ml)at 0° C. was added sodium 2-methylpropan-2-olate (907 mg, 9.43 mmol).The ice-bath was removed and the reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was poured into water andextracted with EtOAc. The combined organic phases were dried overNa₂SO₄, filtered and concentrated in vacuo to give a crude solid. Thesolid was purified by silica gel chromatography (hexane/ethyl acetate,19:1 to 1:1) to concentration in vacuo gave a crude solid, which waspurified by Purif 2 (L) (silica gel, hexane/ethyl acetate, 19:1 to 1:1)to afford ethyl2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoate(266.9 mg, 53% yield) and methyl2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoate(82.6 mg, 17% yield). MS [M+H] for methyl2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoate,found 355.

To a suspension of methyl2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoate(82.6 mg, 0.233 mmol) in THF (6 ml) and MeOH (3 ml) was added 1 N NaOHaqueous solution (0.698 ml, 0.698 mmol), and the mixture was stirred for2 days. After further addition of THF (20 ml) and MeOH (10 ml), themixture was stirred for 16 hours and concentrated in vacuo to give acrude2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoicacid which was used in the next step without further purification. MS[M+H] found 341.

To crude2-(2-chloro-6a-methyl-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)-2-methylpropanoicacid (79 mg, about 0.233 mmol, as a mixture with its methylester) wasadded1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.077 g, 0.28 mmol), Pd(dppf)Cl2-dichloromethane, 1,4-dioxane (3 mL)and NaHCO₃ (sat., 1.5 mL). It was heated under an air-filled balloon (1atm) at 100° C. (bath temperature) for 1.5 hours and then LiOH.H₂O (100mg) was added and heated continued at 80° C. (bath temperature) for 1hour and 40 minutes The mixture was diluted with water and MeOH, passedthrough a microfilter. The filtrate was acidified with concentrated HCl(0.1 mL) to pH<7 and then purified on the HPLC (20-20% of AcCN[containing 0.035% TFA] in water [containing 0.05% TFA], PhenomenexGemini 5 μm C18, 75×30 mm column) to give2-methyl-2-(6a-methyl-2-(4-(3-methylureido)phenyl)-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)propanoicacid as a clear semisolid (10.2 mg). ¹H NMR (400 MHz, METHANOL-d₆) δ ppm1.55 (s, 3H) 1.68 (s, 3H) 1.81 (s, 3H) 2.80 (s, 3H) 3.49 (m, 1H) 3.69(dd, J=12, 4 Hz, 1H) 3.74 (d, J=12 Hz, 1H) 4.05 (d, J=12 Hz, 1H) 4.15(dd, J=12, 4 Hz, 1H) 4.48 (d, J=12 Hz, 1H) 7.62 (d, J=8 Hz, 2H) 8.10 (s,1H) 8.14 (d, J=8 Hz, 2H). MS [M+H] found 455.4.

Example: 211-(4-(5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC (eluting with 20-30%ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using aSunfire Prep 5 μm C18, 75×30 mm column). The clean fractions werecombined and using solid NaHCO₃ adjusted the solution pH>8.0. Theproduct was extracted with ethyl acetate 3 times and the combinedorganic layer was washed with saturated NaCl. The organic layer wasdried with Na₂SO₄, filtered, and concentrated in-vacuo to give the titlecompound (18.9 mg, 37.8% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.24 (d, J=4.04 Hz, 3H) 1.29 (d, J=5.05 Hz, 3H) 1.34 (d,J=8.84 Hz, 3H) 2.62-2.70 (m, 3H) 3.18-3.27 (m, 1H) 3.53-3.74 (m, 3H)3.94-4.10 (m, 4H) 4.10-4.26 (m, 2H) 4.30-4.42 (m, 1H) 6.12-6.22 (m, 1H)7.46-7.53 (m, 2H) 8.17 (dd, J=8.72, 1.14 Hz, 2H) 8.38 (d, J=8.08 Hz, 1H)8.84 (s, 1H). MS [M+H] found 483.4.

Example: 221-(4-(5-((S)-2,3-dihydroxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

Combined2-chloro-5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.201 g, 0.545 mmol),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.166 g, 0.599 mmol), PdCl₂(dppf) (0.080 g, 0.109 mmol), sodiumcarbonate (saturated in water) (1.5 ml, 0.545 mmol) and dioxane (3 ml).The suspension was heated by microwave irradiation at 100° C. for 45minutes. The reaction mixture was filtered via syringe filter andpurified the title compound was purified by preparative HPLC (elutingwith 20-30% ACN (containing 0.035% TFA) in water (containing 0.05% TFA)using a Sunfire Prep 5 μm C18, 75×30 mm column. Product containingfractions were concentrated in vacuo to remove about ½ of the totalvolume and allowed t and let sit at room temperate. After 3 days, thesample was concentrated and purified by HPLC (15-25% of AcCN [containing0.035% TFA] in water [containing 0.05% TFA], Phenomenex Gemini 5 μm C18,75×30 mm column) and the product containing fractions were combined,concentrated in vacuo and lyophilized, affording the title compound(27.9 mg, 11.5% yield) as a pale green solid. ¹H NMR (400 MHz, DMSO-d₆)δ ppm 1.34-1.46 (m, 3H) 2.66 (s, 3H) 3.23-3.36 (m, 1H) 3.36-3.46 (m, 1H)3.59 (t, J=12.00 Hz, 1H) 3.66-3.74 (m, 1H) 3.74-3.87 (m, 2H) 3.88-4.66(m, 7H) 6.12 (br. s., 1H) 7.44-7.58 (m, 2H) 8.09-8.23 (m, 2H) 8.28-8.45(m, 1H) 8.73-8.87 (m, 1H). MS [M+H] found 443.4.

Example: 231-(4-((S)-5-(S)-2,3-dihydroxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylureaand Example: 241-(4-((R)-5-(S)-2,3-dihydroxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

The product of Example 22 (25.7 mg) was separated by SFC (Chiralpak AD-Hcolumn, flow rate=15 mL/min, modifier 30% methanol in CO₂) to giveIsomer 1 (5.3 mg, t=3.29 min) and Isomer 2 (4.3 mg, t=7.63 min).

Example: 251-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

In a 100 mL round bottomed flask containing2,4-dichloropyrimidin-5-amine (1.0 g, 6.10 mmol) in 16.5 mL ofdichloromethane was added dihydro-2H-pyran-4(3H)-one (0.794 g, 7.93mmol), cooled to 0° C. then added the solution of titanium tetrachloride(0.740 ml, 6.71 mmol) in 10 mL of dichloromethane. The reaction wasremoved from the ice bath and with continued stirring, slowly warmed toroom temperature. After 3.5 h, sodium cyanoborohydride (1.15 g, 18.29mmol) was added in 4 equal portions over 10 minutes and the reaction wasstirred at room temperature for 16 h. The suspension was diluted withwater (150 mL) and transferred to an appropriate separatory funnel. Thelayers were separated and then extracted the aqueous layer with MTBE(1×150 mL). The organic layers were combined, washed with sat. NaCl,dried over Na₂SO₄, filtered and concentrated in vacuo affording a clearorange oil. The crude oil was purified by silica chromatography (30%EtOAc/Hexanes); the appropriate fractions were combined and concentratedin vacuo to afford2,4-dichloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine (0.336 g, 60%pure, 22% yield). MS [M+H] found 249.1.

In a 100 mL round bottomed flask containing2,4-dichloro-N-(tetrahydro-2H-pyran-4-yl)pyrimidin-5-amine (0.336 g,1.354 mmol) in 2.0 mL of DMSO was added morpholine-3-carboxylic acidhydrochloride (0.295 g, 1.761 mmol) and DIPEA (1.183 ml, 6.77 mmol). Thereaction mixture was stirred at 100° C. for 16 h. The reaction wascooled to room temperature, diluted with 30 mL of water, transferred toan appropriate separatory funnel and extracted with EtOAc (3×25 mL). Theorganic layers were combined, washed with sat. NaCl, dried over Na₂SO₄,filtered and concentrated in vacuo affording an oil. The oil wassuspended in 10 mL of Et₂O, added 2 drops of EtOH and sonicated until ayellow precipitate appeared. Let mixture sit at room temperature for 1h, collected solids by vacuum filtration, washed with additional Et₂O,hexanes and dried under high vacuum affording2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one.(90 mg, 20.4% yield) as a light yellow solid. ¹H NMR (400 MHz,CHLOROFORM-d) δ ppm 1.54-1.65 (m, 1H) 1.70 (dd, J=12.88, 2.02 Hz, 1H)2.51-2.70 (m, 2H) 3.03 (ddd, J=13.58, 12.32, 3.92 Hz, 1H) 3.41-3.66 (m,4H) 4.03 (dd, J=11.87, 3.79 Hz, 4H) 4.32-4.47 (m, 2H) 4.59 (tt, J=12.47,4.07 Hz, 1H) 8.05 (s, 1H). MS [M+H] found 325.2.

In a microwave reaction vial,2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.0258 g, 0.079 mmol),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.024 g, 0.087 mmol), PdCl₂(dppf) (0.012 g, 0.016 mmol) and sodiumbicarbonate (saturated solution) (0.3 ml, 0.079 mmol) were suspended indioxane (0.794 ml). The suspension was heated by microwave irradiationat 100° C. for 1 h. The reaction mixture was cooled and purified bypreparative HPLC (eluting with 15-25% ACN (containing 0.035% TFA) inwater (containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mmcolumn). The clean fractions were combined, concentrated in vacuo andlyophilized, affording the title compound (10.0 mg, 28.7% yield) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.56-1.73 (m, 2H) 2.61-2.70(m, 3H) 3.01 (td, J=12.82, 3.66 Hz, 1H) 3.35-3.46 (m, 1H) 3.46-3.62 (m,3H) 3.74-3.89 (m, 1H) 3.89-4.04 (m, 2H) 4.14-4.30 (m, 4H) 4.38 (ddt,J=11.81, 7.89, 4.04, 4.04 Hz, 1H) 4.48 (d, J=12.13 Hz, 1H) 6.13 (br. s.,1H) 7.52 (d, J=8.84 Hz, 2H) 8.13-8.20 (m, 2H) 8.40 (s, 1H) 8.81 (s, 1H).MS [M+H] found 439.4.

To a 20 mL vial containing2-chloro-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.0907 g, 0.279 mmol) was added DMSO (0.5 mL); placed in a dryice-acetone bath and then added sodium tert-butoxide (0.030 g, 0.307mmol) followed by DMSO (0.5 mL) and iodomethane (0.019 ml, 0.307 mmol).The dry ice-acetone bath was removed and the mixture was allowed to warmup to room temperature and stirred for 16 h. The reaction was dilutedwith 10 mL of water and vigorously stirred at room temperature.Collected rust/orange solids by vacuum filtration, washed withadditional water and dried under high vacuum affording2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(46.0 mg, 48.4% yield) as a yellow solid. ¹H NMR (400 MHz, CHLOROFORM-d)δ ppm 1.41 (d, J=0.76 Hz, 3H) 2.48-2.72 (m, 2H) 3.17-3.34 (m, 1H)3.41-3.77 (m, 5H) 3.94-4.19 (m, 6H) 4.61 (tt, J=12.38, 4.29 Hz, 1H)7.98-8.14 (m, 1H). MS [M+H] found 339.3.

In a microwave reaction vial,2-chloro-6a-methyl-5-(tetrahydro-2H-pyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(0.046 g, 0.136 mmol),1-methyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(0.041 g, 0.149 mmol), PdCl₂(dppf) (0.020 g, 0.027 mmol) and sodiumbicarbonate (saturated solution) (0.3 ml, 0.136 mmol) were suspended indioxane (1.36 ml). The suspension was heated by microwave irradiation at100° C. for 1 hour, then heated by microwave irradiation at 120° C. foran additional 30 minutes. The reaction was purified by preparative HPLC(eluting with 20-30% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). Productcontaining fractions were combined, concentrated in vacuo andlyophilized, affording the title compound (41.4 mg, 67.4% yield) as anoff-white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32 (s, 3H) 1.55-1.74(m, 2H) 2.62-2.70 (m, 3H) 3.25 (td, J=13.14, 4.04 Hz, 1H) 3.34-3.45 (m,1H) 3.47-3.72 (m, 3H) 3.87-4.00 (m, 3H) 4.06 (dd, J=11.62, 3.79 Hz, 2H)4.19 (dd, J=13.77, 2.15 Hz, 3H) 6.01-6.24 (m, 1H) 7.48-7.57 (m, 2H)8.13-8.22 (m, 2H) 8.48 (s, 1H) 8.81 (s, 1H). MS [M+H] found 453.4.

Example: 26(S)-1-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 27(R)-1-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The product of Example 25 (38.3 mg) was separated by SFC (Chiralpak AD-Hcolumn, flow rate=55 mL/min, modifier 45% methanol) to give Isomer 1(10.0 mg, t=1.86 min) and Isomer 2 (10.2 mg, t=3.38 min).

Example: 281-methyl-3-(4-(6a-methyl-5-neopentyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC (eluting with 30-35%ACN (containing 0.035% TFA) in water (containing 0.05% TFA) using aSunfire Prep 5 μm C18, 75×30 mm column). The clean fractions werecombined, concentrated in vacuo and lyophilized, affording the titlecompound (9.4 mg, 2.3% yield) as a light yellow solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.90 (s, 9H) 1.35 (s, 3H) 2.62-2.70 (m, 3H) 3.27 (td,J=13.14, 3.79 Hz, 2H) 3.60-3.69 (m, 1H) 3.88 (s, 2H) 4.00 (d, J=11.62Hz, 1H) 4.07 (dd, J=11.24, 3.66 Hz, 1H) 4.20 (d, J=11.62 Hz, 1H) 6.08(br. s., 1H) 7.50 (d, J=8.84 Hz, 2H) 8.14-8.21 (m, 2H) 8.46 (s, 1H) 8.74(s, 1H). MS [M+H] found 439.4.

Example: 291-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydrofuran-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 25. Afterthe microwave irradiation the title compound was purified by preparativeHPLC (eluting with 15-20% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The clean fractions were combined, concentrated in vacuo andlyophilized, affording the title compound (5.5 mg, 27.2% yield) as apale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.43 (m, 3H)1.98-2.10 (m, 1H) 2.11-2.28 (m, 2H) 2.61-2.71 (m, 3H) 3.23-3.36 (m, 1H)3.52-3.77 (m, 3H) 3.80-4.10 (m, 4H) 4.16-4.30 (m, 2H) 5.34-5.48 (m, 1H)6.15 (br. s., 1H) 7.48-7.58 (m, 2H) 8.17 (d, J=8.84 Hz, 2H) 8.37 (s, 1H)8.83-8.92 (m, 1H). MS [M+H] found 439.4.

Example: 301-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydrofuran-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 25. Afterthe microwave irradiation the title compound was purified by preparativeHPLC (eluting with 23-25% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The clean fractions were combined, concentrated in vacuo andlyophilized, affording the title compound (34.4 mg, 24% yield) as alight yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.36-0.45 (m, 2H)0.57-0.69 (m, 2H) 1.38 (d, J=7.83 Hz, 3H) 2.23 (d, J=7.33 Hz, 2H) 3.30(t, J=12.63 Hz, 1H) 3.51-3.78 (m, 3H) 3.79-4.12 (m, 4H) 4.16-4.36 (m,2H) 5.35-5.50 (m, 1H) 5.57-5.73 (m, 1H) 6.57 (br. s., 1H) 7.48-7.59 (m,2H) 8.12-8.22 (m, 2H) 8.36 (s, 1H) 8.71 (d, J=5.56 Hz, 1H). MS [M+H]found 465.4.

Example: 311-ethyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 25. Afterthe microwave irradiation the title compound was purified by preparativeHPLC (eluting with 20-30% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The product containing fractions were combined, concentrated in vacuoand lyophilized, affording the title compound (41.4 mg, 67.4% yield) asa white solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.06 (t, J=7.07 Hz, 3H)1.30 (s, 3H) 1.54-1.73 (m, 2H) 2.56-2.71 (m, 1H) 3.05-3.15 (m, 2H)3.19-3.30 (m, 1H) 3.39 (t, J=10.99 Hz, 1H) 3.47-3.72 (m, 3H) 3.86-4.00(m, 3H) 4.06 (dd, J=11.49, 3.66 Hz, 1H) 4.15 (d, J=11.62 Hz, 1H)4.34-4.49 (m, 2H) 6.22 (br. s., 1H) 7.51 (d, J=8.84 Hz, 2H) 8.17 (d,J=8.84 Hz, 2H) 8.51 (s, 1H) 8.74 (s, 1H). MS [M+H] found 467.4.

Example: 321-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 25. Afterthe microwave irradiation the title compound was purified by preparativeHPLC (eluting with 23-30% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The product containing fractions were combined, concentrated in vacuoand lyophilized, affording the title compound (64.3 mg, 32.5% yield) asa pale yellow solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.36-0.46 (m, 2H)0.59-0.69 (m, 2H) 1.30 (s, 3H) 1.55-1.73 (m, 2H) 2.41-2.48 (m, 1H)2.52-2.70 (m, 2H) 3.24 (td, J=13.14, 4.04 Hz, 1H) 3.33-3.45 (m, 1H)3.47-3.73 (m, 4H) 3.86-4.22 (m, 4H) 4.34-4.50 (m, 2H) 6.50 (br. s., 1H)7.52 (d, J=8.84 Hz, 2H) 8.13-8.23 (m, 1H) 8.51 (s, 1H) 8.62 (s, 1H). MS[M+H] found 479.4.

Example: 33(S)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 34(R)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The product of Example 32 (59 mg) was separated by SFC (Chiral pak AD-Hcolumn, flow rate=50 mL/min, modifier 35% iPrOH) to give Isomer 1 (12.0mg, t=1.66 min) and Isomer 2 (15.8 mg, t=2.50 min).

Example: 351-(4-[5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea

The title compound was prepared by method similar to Example 1, exceptthe title compound was chromatographed by silica gel (hexane/ethylacetate/methanol, 80:20:0 to 0:100:0 to 0:17:3) and then this resultingsolid was triturated with EtOAc/hexane (1:1), collected by filtrationand dried to afford the title compound (67.2 mg, 0.153 mmol, 63% yield)as a beige solid. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.31-1.38 (m, 3H)1.75-1.88 (m, 2H) 2.66 (d, J=4.55 Hz, 2H) 3.18-3.32 (m, 5H) 3.38 (t,J=6.06 Hz, 2H) 3.52-3.63 (m, 1H) 3.67 (d, J=11.37 Hz, 1H) 3.84-4.11 (m,4H) 4.18 (dd, J=13.64, 2.27 Hz, 1H) 6.05 (q, J=4.46 Hz, 1H) 7.48 (d,J=8.84 Hz, 2H) 8.18 (d, J=8.84 Hz, 2H) 8.24 (s, 1H) 8.70 (s, 1H). MS[M+H] found 441.

Example: 36(S)-1-(4-[5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylureaand Example: 37(R)-1-(4-[5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea

The product of 35 (58 mg) was separated by chiral SFC (Chiralpak IAcolumn, flowrate=1.25 mL/min, modifier 16% methanol/dichloromethane(80/20) in liquid CO₂ to give Isomer 1 (9.2 mg, t=7.65 min) and Isomer 2(8.0 mg, t=10.6 min).

Example: 381-(4-[5-(2-methoxyethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC (eluting with agradient of 15-40% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column) to afford thetitle compound (22.5 mg, 0.053 mmol, 37% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) δ ppm 1.33 (s, 3H) 2.66 (d, J=4.55 Hz, 3H) 3.19-3.33(m, 4H) 3.52-3.71 (m, 4H) 3.93-4.23 (m, 5H) 6.01-6.10 (m, 1H) 7.44-7.52(m, 2H) 8.14-8.21 (m, 2H) 8.32 (s, 1H) 8.70 (s, 1H). MS [M+H] found 427.

Example: 391-ethyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC (eluting with agradient of 20-45% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column) to afford thetitle compound (40.8 mg, 0.090 mmol, 49.3% yield) as a white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 1.06 (t, J=7.07 Hz, 3H) 1.34 (s, 3H)1.75-1.87 (m, 2H) 3.06-3.18 (m, 2H) 3.18-3.30 (m, 4H) 3.38 (t, J=6.06Hz, 2H) 3.52-3.63 (m, 1H) 3.67 (d, J=11.62 Hz, 1H) 3.85-4.10 (m, 4H)4.13-4.24 (m, 1H) 6.15 (t, J=5.56 Hz, 1H) 7.47 (d, J=8.84 Hz, 2H) 8.17(d, J=8.84 Hz, 2H) 8.23 (s, 1H) 8.61 (s, 1H). MS [M+H] found 455.

Example: 401-cyclopropyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC (eluting with agradient of 20-45% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column) to afford thetitle compound (37.1 mg, 0.080 mmol, 43% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.41 (m, 2H) 0.64 (m, 2H) 1.34 (s, 3H)1.75-1.87 (m, 2H) 2.51-2.61 (m, 1H) 3.19-3.29 (m, 4H) 3.38 (t, J=6.06Hz, 2H) 3.52-3.63 (m, 1H) 3.67 (d, J=11.62 Hz, 1H) 3.85-4.11 (m, 4H)4.13-4.24 (m, 1H) 6.42 (d, J=2.78 Hz, 1H) 7.43-7.54 (m, 2H) 8.14-8.21(m, 2H) 8.24 (s, 1H) 8.49 (s, 1H). MS [M+H] found 467.

Example: 41(S)-1-cyclopropyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 42(R)-1-cyclopropyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The product of 40 (26.9 mg) was separated by chiral SFC (Chiralpak AD-Hcolumn, flowrate=1.25 mL/min, modifier 40% methanol containing 10 mMNH₄OAc in liquid CO₂ to give Isomer 1 (12.1 mg, t=1.59 min) and Isomer 2(12.5 mg, t=4.30 min).

Example: 431-(4-(5-(2-ethoxyethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

The title compound was prepared by method similar to Example 1, exceptthe title compound was purified by preparative HPLC (eluting with agradient of 15-40% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column) to afford thetitle compound (43.9 mg, 0.100 mmol, 52.4% yield) as an off-white solid.¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04 (t, J=6.95 Hz, 3H) 1.33 (s, 3H)2.66 (d, J=4.80 Hz, 3H) 3.18-3.32 (m, 1H) 3.36-3.50 (m, 2H) 3.51-3.71(m, 4H) 3.94-4.29 (m, 5H) 6.01-6.11 (m, 1H) 7.44-7.53 (m, 2H) 8.13-8.22(m, 2H) 8.33 (s, 1H) 8.70 (s, 1H). MS [M+H] found 441.

Example: 441-(4-(5-(2-hydroxy-2-methylpropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea

To a mixture of methyl 2-hydroxy-2-methylpropanoate (5.04 g, 42.7 mmol)and 3,4-dihydro-2H-pyran (5.85 ml, 64.0 mmol) in dichloromethane (40 ml)was added pyridine 4-methylbenzenesulfonate (0.536 g, 2.13 mmol) and thereaction mixture was stirred for 1.5 hours. The reaction mixture waspoured into water and extracted with Et₂O. The organic layers were driedover Na₂SO₄ filtered, and concentrated in vacuo to give a crude oil. Thecrude residue was purified by silica gel chromatography (hexane/ethylacetate, 100:0 to 17:3) to afford methyl2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (7.30 g, 36.1 mmol,85% yield) as a colorless oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35 (s,3H) 1.36-1.55 (m, 7H) 1.57-1.81 (m, 2H) 3.32-3.42 (m, 1H) 3.62 (s, 3H)3.72-3.85 (m, 1H) 4.65-4.75 (m, 1H).

To a solution of methyl2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanoate (1.25 g, 6.16 mmol)in THF (20 ml) under nitrogen was added portionwise lithium aluminiumhydride (0.246 g, 6.16 mmol) at 0° C. and the reaction mixture wasstirred 2 h, followed by slow addition of Na₂SO₄.10H₂O (1.98 g, 6.16mmol). After 30 minutes of stirring at 0° C. to room temperature, theinsoluble materials were filtered off. The filtrate was concentrated invacuo to give 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol (1.16g, 6.68 mmol, quant.) as a colorless oil which was used in the next stepwithout further purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11 (s,6H) 1.29-1.62 (m, 5H) 1.67-1.80 (m, 1H) 3.19-3.31 (m, 2H) 3.34-3.43 (m,1H) 3.77-3.88 (m, 1H) 4.40 (t, J=5.94 Hz, 1H) 4.75-4.81 (m, 1H).

To a suspension of 2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propan-1-ol(1.16 g, 6.68 mmol) in dichloromethane (20 ml) at 0° C. was addedportionwise Dess-Martin periodinane (3.26 g, 7.68 mmol), and thereaction mixture was stirred at the same temperature for 20 minutes,followed by addition of saturated aqueous NaHCO₃ and Na₂S₂O₃. Theresulting mixture was stirred for 3 hours and the reaction mixture wasextracted with Et₂O. The combined organic phases were dried andconcentrated in vacuo to give2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanal (958 mg, 5.56 mmol, 83%yield) as a colorless oil which was used in the next step withoutfurther purification. ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.18 (s, 3H) 1.23(s, 3H) 1.33-1.85 (m, 6H) 3.32-3.44 (m, 1H) 3.73-3.89 (m, 1H) 4.61-4.70(m, 1H) 9.44 (s, 1H).

To a mixture of 2,4-dichloropyrimidin-5-amine (542 mg, 3.31 mmol) and2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propanal (740 mg, 4.30 mmol) indichloromethane (10 ml) at 0° C. was added dropwise a solution oftitanium tetrachloride (0.401 ml, 3.64 mmol) in dichloromethane (4 ml).After the reaction mixture was stirred at room temperature for 2 hours.Sodium cyanoborohydride (656 mg, 9.92 mmol) was added portionwise andthe reaction mixture was stirred at room temperature for 16 hours. Afterthe reaction mixture was diluted with dichloromethane, the reactionmixture was poured carefully into NaHCO₃ aqueous solution. EtOAc wasadded and then the insoluble materials were filtered off. The phases ofthe filtrate were separated, and the aqueous phase was extracted withEtOAc. The combined organic phases were washed with water, dried andconcentrated in vacuo to give a crude oil. The crude residue waspurified by silica gel chromatography (hexane/ethyl acetate, 19:1 to2:3) to afford 1-(2,4-dichloropyrimidin-5-ylamino)-2-methylpropan-2-ol(315 mg, 1.34 mmol, 40% yield) as a yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.15 (s, 6H) 3.16 (d, J=6.32 Hz, 2H) 4.64 (s, 1H)5.60-5.68 (m, 1H) 8.31 (s, 1H).

To a mixture of 1-(2,4-dichloropyrimidin-5-ylamino)-2-methylpropan-2-ol(258 mg, 1.09 mmol) and 3,4-dihydro-2H-pyran (0.200 ml, 2.18 mmol) indichloromethane (7 ml) was added pyridine 4-methylbenzenesulfonate (13.7mg, 0.055 mmol) and the reaction mixture was stirred for 16 hours. Thereaction mixture was poured into water and extracted with Et₂O. Theorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give a crude oil. The crude residue was purified by silica gelchromatography (hexane/ethyl acetate, 100:0 to 3:1) to afford2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine(315 mg, 0.982 mmol, 90% yield) as a pale yellow oil. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.18 (s, 3H) 1.23 (s, 3H) 1.25-1.75 (m, 6H) 3.27-3.32 (m,2H) 3.37-3.49 (m, 1H) 3.69-3.83 (m, 1H) 4.74-4.86 (m, 1H) 5.75 (t,J=6.32 Hz, 1H) 8.36 (s, 1H).

To a mixture of2,4-dichloro-N-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrimidin-5-amine(315 mg, 0.982 mmol) and morpholine-3-carboxylic acid hydrochloride (247mg, 1.47 mmol) in DMSO (6 ml) was added diisopropylethylamine (0.686 ml,3.93 mmol), and the reaction mixture was stirred at 95° C. for 4 hours.The reaction mixture was poured into water and extracted with EtOAc. Theorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give a crude oil. The crude residue was chromatographed bysilica gel (hexane/ethyl acetate, 19:1 to 1:1) to afford2-chloro-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(96.2 mg, 0.242 mmol, 25% yield) as a pale yellow oil which was used inthe next reaction without further purification. MS [M+H] found 397.

To a mixture of2-chloro-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(96.2 mg, 0.242 mmol) and iodomethane (0.076 ml, 1.21 mmol) in DMSO (4ml) at 0° C. was added sodium 2-methylpropan-2-olate (46.6 mg, 0.485mmol). The ice-bath was removed and the reaction mixture was stirred atroom temperature for 16 h, followed by being poured into water.Extraction with EtOAc, washing with water, drying and concentration invacuo gave crude2-chloro-6a-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(133 mg, 0.322 mmol) as a red oil which was used without furtherpurification. MS [M+H] found 411.

To a solution of2-chloro-6a-methyl-5-(2-methyl-2-(tetrahydro-2H-pyran-2-yloxy)propyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(133 mg, 0.322 mmol) in THF (3 ml) was added 1 N HCl aqueous solution (1ml, 1.000 mmol) and the reaction mixture was stirred for 1 h, followedby being poured into NaHCO₃ aqueous solution. Extraction with EtOAc,drying over Na2SO4 and concentration in vacuo gave crude2-chloro-5-(2-hydroxy-2-methylpropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(84.9 mg, 0.260 mmol, 81% yield) as a yellow oil which was used in thenext step without further purification. MS [M+H] found 327.

A mixture of2-chloro-5-(2-hydroxy-2-methylpropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(84.9 mg, 0.260 mmol),1-methyl-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)phenyl]-urea(143 mg, 0.520 mmol), saturated aqueous NaHCO₃ (1 ml) and PdCl₂(dppf)(17.0 mg, 0.021 mmol) in 1,4-dioxane (2 ml) was irradiated in themicrowave at 110° C. for 30 minutes The reaction mixture was dilutedwith THF and passed through 0.45 μM PTFE syringe filter (washed withsmall amount of MeOH). The filtrate was purified by preparative HPLC(eluting with a gradient of 20-20% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The fractions containing the desired product were combined and wereevaporated under reduced pressure. Then NaHCO₃ aqueous solution wasadded (in order to adjust the pH to basic) and extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuo to afford a crude solid. The solid was trituratedwith hexane/ethyl acetate (3:1), collected by filtration, rinsed withhexane/ethyl acetate (3:1) and dried to afford the title compound (21.1mg, 0.048 mmol, 18.4% yield) as a pale beige solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.14 (s, 3H) 1.15 (s, 3H) 1.35 (s, 3H) 2.66 (d, J=4.55Hz, 3H) 3.19-3.33 (m, 1H) 3.52-3.80 (m, 3H) 3.94-4.11 (m, 3H) 4.12-4.22(m, 1H) 4.67 (s, 1H) 6.00-6.10 (m, 1H) 7.48 (d, J=8.84 Hz, 2H) 8.17 (d,J=8.84 Hz, 2H) 8.58 (s, 1H) 8.68 (s, 1H). MS [M+H] found 441.

Example: 451-cyclopropyl-3-(4-[5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)urea

To a mixture of 2,4-dichloropyrimidin-5-amine (1.58 g, 9.63 mmol) anddihydro-2H-thiopyran-4(3H)-one (1.45 g, 12.5 mmol) in dichloromethane(50 ml) at 0° C. was added dropwise a 1 M solution of titaniumtetrachloride (10.6 ml, 10.6 mmol) in dichloromethane. After thereaction mixture was stirred at room temperature for 2 h, sodiumcyanoborohydride (1.91 g, 28.9 mmol) was added in single portion and thereaction mixture was stirred at room temperature for 16 hours. After thereaction mixture was diluted with dichloromethane, the reaction mixturewas poured carefully into iced-saturated NaHCO₃ solution. EtOAc wasadded and then the insoluble materials were filtered off. The phases ofthe filtrate were separated, and the aqueous phase was extracted withEtOAc. The combined organic phases were washed with water and saturatedNaCl, dried with Na₂SO₄ and concentrated in vacuo to give a crude oil.The crude residue was purified by silica gel chromatography(hexane/ethyl acetate, 100:0 to 3:1) to afford2,4-dichloro-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-5-amine (864 mg,3.27 mmol, 34% yield) as a yellow oil. ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.59-1.76 (m, 2H) 2.07-2.20 (m, 2H) 2.58-2.69 (m, 2H) 2.70-2.85 (m, 2H)3.42-3.57 (m, 1H) 5.78 (d, J=8.84 Hz, 1H) 8.25 (s, 1H). MS [M+H] 264.

To a mixture of2,4-dichloro-N-(tetrahydro-2H-thiopyran-4-yl)pyrimidin-5-amine (864 mg,3.27 mmol) and morpholine-3-carboxylic acid hydrochloride (822 mg, 4.91mmol) in DMSO (15 ml) was added diisopropylethylamine (2.29 ml, 13.1mmol), and the reaction mixture was stirred at 95° C. for 4 hours. Thereaction mixture was poured into water and extracted with EtOAc. Theorganic layers were dried over Na₂SO₄, filtered and concentrated invacuo to give a crude solid. The solid was chromatographed by silica gel(hexane/ethyl acetate, 19:1 to 3:2) to afford partially purified2-chloro-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(83.6 mg, 0.245 mmol, 7.5% yield) as a white solid. MS [M+H] found 341.

To a mixture of2-chloro-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(83.6 mg, 0.245 mmol) and iodomethane (0.077 ml, 1.226 mmol) in DMSO (3ml) at 0° C. was added sodium 2-methylpropan-2-olate (47.1 mg, 0.491mmol). The ice-bath was removed and the reaction mixture was stirred atroom temperature for 16 hours. The reaction mixture was poured intowater and extracted with EtOAc. The organic layers were washed withwater (containing Na₂S₂O₃), dried and concentrated in vacuo to give acrude oil. The crude residue was purified by silica gel chromatography(hexane/ethyl acetate, 19:1 to 1:1) to afford2-chloro-6a-methyl-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(9.4 mg, 0.026 mmol, 11% yield) as a colorless oil. MS [M+H] found 355.

To a solution of2-chloro-6a-methyl-5-(tetrahydro-2H-thiopyran-4-yl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(9.4 mg, 0.026 mmol) in MeOH (1 ml) at 0° C. was added dropwise asolution of oxone (40.7 mg, 0.066 mmol) in water (1 ml), and thereaction mixture was stirred at room temperature for 16 h, followed bysolvent removal in vacuo. The residue was partitioned between EtOAc andwater. The phases were separated and the aqueous phase was extractedwith EtOAc. The combined organic phases were dried and concentrated invacuo to give2-chloro-5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one(6.5 mg, 0.017 mmol, 63% yield) as a white solid. This was used in thenext step without further purification. MS [M+H] found 387.

A mixture of2-chloro-5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6a,7,9,10-tetrahydro[1,4]oxazino[3,4-h]pteridin-6(5H)-one(6.50 mg, 0.017 mmol),1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(8.63 mg, 0.029 mmol), saturated aqueous NaHCO₃ (0.75 ml) andPdCl₂(dppf) (1.10 mg, 1.34 μmmol) in 1,4-dioxane (1 ml) was irradiatedin the microwave at 110° C. for 30 minutes The reaction mixture wasdiluted with THF and passed through 0.45 mM PTFE syringe filter (washedwith small amount of THF). The filtrate was purified by preparative HPLC(eluting with a gradient of 15-40% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The fractions containing the desired product were combined and wereevaporated under reduced pressure. Then NaHCO₃ aqueous solution wasadded (in order to adjust the pH to basic) and extracted with EtOAc. Thecombined organic phases were dried over Na₂SO₄, filtered andconcentrated in vacuo to afford the title compound (6.2 mg, 0.012 mmol,70% yield) as a white solid. ¹H NMR (400 MHz, DMSO-d₆) d ppm 0.36-0.45(m, 2H) 0.59-0.69 (m, 2H) 1.32 (s, 3H) 1.93-2.17 (m, 2H) 2.51-2.60 (m,1H) 2.85-3.76 (m, 9H) 3.91-3.99 (m, 1H) 4.01-4.10 (m, 1H) 4.14-4.25 (m,1H) 4.45-4.62 (m, 1H) 6.58 (br. s., 1H) 7.49-7.56 (m, 2H) 8.16-8.24 (m,2H) 8.49 (s, 1H) 8.75 (s, 1H). MS [M+H] found 527.

Example: 461-cyclopropyl-3-(4-(6a-methyl-5-(3-(methylsulfonyl)propyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The title compound was prepared by method similar to Example 1 using3-(methylsulfonyl)propyl-4-methylbenzenesulfonate, except the titlecompound was purified by preparative HPLC (eluting with a gradient of15-40% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) usinga Sunfire Prep 5 μm C18, 75×30 mm column) to afford the title compound(38.9 mg, 0.076 mmol, 32% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 0.37-0.46 (m, 2H) 0.60-0.69 (m, 2H) 1.37 (s, 3H)1.91-2.05 (m, 2H) 2.47-2.59 (m, 1H) 3.00 (s, 3H) 3.19-3.34 (m, 3H)3.52-3.64 (m, 1H) 3.71 (d, J=11.37 Hz, 1H) 3.92-4.12 (m, 4H) 4.15-4.26(m, 1H) 6.46 (d, J=2.53 Hz, 1H) 7.45-7.55 (m, 2H) 8.15-8.24 (m, 2H) 8.33(s, 1H) 8.54 (s, 1H). MS [M+H] found 515.

Example: 471-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

To a mixture of2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (822mg, 3.42 mmol), chloroacetone (0.429 ml, 5.12 mmol) in DMF (10 ml) wasadded K₂CO₃ (1.42 g, 10.3 mmol) and the reaction mixture was stirred atroom temperature for 2 days. The reaction mixture was poured into waterand extracted with EtOAc. The organic layers were washed with water andsaturated aqueous NaCl, dried and concentrated in vacuo to give a crudesolid. The crude residue was triturated with hexane/ethyl acetate (3:1),collected by filtration, rinsed with hexane/ethyl acetate (3:1) anddried to afford2-chloro-5-(2-oxopropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(737 mg, 2.48 mmol, 73% yield) as a pale brown solid. MS [M+H] found297.

To a solution of2-chloro-5-(2-oxopropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(736 mg, 2.48 mmol) in dichloromethane (15 ml) at 0° C. was addeddropwise a solution of DAST (0.984 ml, 7.45 mmol) in dichloromethane (3ml), and the reaction mixture was stirred at room temperature for 1hour. Additional DAST (0.984 ml, 7.45 mmol) was added and the reactionmixture was stirred for 5 hours. Additional DAST (1.97 ml, 14.9 mmol)was added and the reaction mixture was stirred for 3 hours. Further DAST(3.94 ml, 29.8 mmol) was added and the reaction mixture was stirred for16 hours. After the reaction mixture was cooled to 0° C., saturatedaqueous NaHCO₃ was carefully added. The resulting mixture was stirredfor 15 minutes and then extracted with EtOAc. The combined organicphases were washed with water, dried over Na₂SO₄, filtered andconcentrated in vacuo to give a crude solid. The solid was purified bysilica gel chromatography (hexane/ethyl acetate, 19:1 to 2:3) to afford2-chloro-5-(2,2-difluoropropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(466 mg, 1.46 mmol, 59% yield) as a white solid. MS [M+H] found 319.

To a mixture of2-chloro-5-(2,2-difluoropropyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(466 mg, 1.46 mmol) and iodomethane (0.365 ml, 5.84 mmol) in DMSO (8 ml)at 0° C. was added sodium 2-methylpropan-2-olate (211 mg, 2.19 mmol).The ice-bath was removed and the reaction mixture was stirred at roomtemperature for 16 hours. The reaction mixture was poured into water andextracted with EtOAc. The organic layers were washed with water(containing Na₂S₂O₃), dried and concentrated in vacuo to give a crudesolid. The solid was purified by silica gel chromatography (hexane/ethylacetate, 19:1 to 2:1) to afford2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(264 mg, 0.793 mmol, 54% yield) as a white solid. MS [M+H] found 333.

A mixture of2-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(260 mg, 0.782 mmol),1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(402 mg, 1.33 mmol), saturated aqueous NaHCO₃ (2 ml) and PdCl₂(dppf)(51.1 mg, 0.063 mmol) in 1,4-dioxane (5 ml) was irradiated in themicrowave at 110° C. for 30 minutes The reaction mixture was dilutedwith THF and passed through 0.45 μM PTFE syringe filter (washed withsmall amount of THF). The filtrate was purified by preparative HPLC(eluting with a gradient of 20-45% ACN (containing 0.035% TFA) in water(containing 0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column).The fractions containing the desired product were combined and wereevaporated under reduced pressure. Then NaHCO₃ aqueous solution wasadded (in order to adjust the pH to basic) and extracted with EtOAc (THFwas added to dissolve the precipitate). The combined organic phases weredried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound (164 mg, 0.347 mmol, 44% yield) as an off-white solid. ¹HNMR (400 MHz, DMSO-d₆) δ ppm 0.35-0.45 (m, 2H) 0.58-0.71 (m, 2H) 1.36(s, 3H) 1.70 (t, J=19.20 Hz, 3H) 2.50-2.61 (m, 1H) 3.19-3.31 (m, 1H)3.53-3.73 (m, 2H) 3.94-4.11 (m, 2H) 4.12-4.25 (m, 1H) 4.34-4.52 (m, 1H)4.52-4.70 (m, 1H) 6.46 (d, J=2.53 Hz, 1H) 7.45-7.55 (m, 2H) 8.14-8.23(m, 2H) 8.39 (s, 1H) 8.54 (s, 1H). MS [M+H] found 473.

Example: 48(S)-1-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 49(S)-1-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 50(R)-1-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The product of Example 47 (164 mg) was separated by chiral SFC(Chiralpak AD-H column, flowrate=1.25 mL/min, modifier 23% 1-propanolcontaining 10 mM NH₄OAc in liquid CO₂ to give Isomer 1 (68.0 mg, t=2.54min) and Isomer 2 (62.3 mg, t=3.49 min).

Example: 511-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(2,2,2-trifluoroethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

To a solution of2-chloro-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one (363mg, 1.509 mmol) in DMF (6 ml) at 0° C. was added NaH (72.4 mg, 1.81mmol). After 15 minutes of stirring at 0° C., a solution of2,2,2-trifluoroethyl trifluoromethanesulfonate (525 mg, 2.26 mmol) inDMF (1 ml) was slowly added. The reaction mixture was stirred at roomtemperature for 1.5 hours. The reaction mixture was poured into waterand extracted with EtOAc. The organic layers were washed with water,dried over Na₂SO₄ and concentrated in vacuo to give a crude oil. Thecrude residue was purified by silica gel chromatography (hexane/ethylacetate, 19:1 to 1:1) to afford2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(373 mg, 1.16 mmol, 77% yield) as a yellow solid. MS [M+H] found 323.

To a mixture of2-chloro-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(768 mg, 2.38 mmol) and iodomethane (0.595 ml, 9.52 mmol) in DMSO (15ml) at 0° C. was added sodium 2-methylpropan-2-olate (343 mg, 3.57mmol). The ice-bath was removed and the reaction mixture was stirred atroom temperature for 16 hours. The reaction mixture was poured intowater and extracted with EtOAc. The organic layers were washed withwater (containing Na₂S₂O₃), dried and concentrated in vacuo to give acrude oil. The crude residue was purified by silica gel chromatography(hexane/ethyl acetate, 19:1 to 11:9) to afford2-chloro-6a-methyl-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(191 mg, 0.566 mmol, 24% yield) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ ppm 1.41 (s, 3H) 3.17-3.28 (m, 1H) 3.55 (td, J=12.13, 3.03Hz, 1H) 3.68 (d, J=11.62 Hz, 1H) 3.89-4.07 (m, 3H) 4.75-5.04 (m, 2H)8.31 (s, 1H). MS [M+H] found 337.

A mixture of2-chloro-6a-methyl-5-(2,2,2-trifluoroethyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(292 mg, 0.868 mmol),1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(446 mg, 1.48 mmol), saturated aqueous NaHCO₃ (2 ml) and PdCl₂(dppf)(56.7 mg, 0.069 mmol) in 1,4-dioxane (4 ml) was irradiated in microwaveat 110° C. for 30 minutes The reaction mixture was diluted with THF andpassed through 0.45 μM PTFE syringe filter (washed with small amount ofTHF). The filtrate was purified by preparative HPLC (eluting with agradient of 25-50% ACN (containing 0.035% TFA) in water (containing0.05% TFA) using a Sunfire Prep 5 μm C18, 75×30 mm column). Thefractions containing the desired product were combined and wereevaporated under reduced pressure. Then NaHCO₃ aqueous solution wasadded (in order to adjust the pH to basic) and extracted with EtOAc (THFwas added to dissolve the precipitate). The combined organic phases weredried over Na₂SO₄, filtered and concentrated in vacuo to afford thetitle compound (206 mg, 0.432 mmol, 50% yield) as a white solid. ¹H NMR(400 MHz, DMSO-d₆) ppm 0.37-0.45 (m, 2H) 0.59-0.69 (m, 2H) 1.37 (s, 3H)2.51-2.60 (m, 1H) 3.22-3.33 (m, 1H) 3.55-3.73 (m, 2H) 3.98-4.11 (m, 2H)4.15-4.24 (m, 1H) 4.80-4.94 (m, 1H) 4.94-5.11 (m, 1H) 6.43-6.50 (m, 1H)7.46-7.54 (m, 2H) 8.15-8.23 (m, 2H) 8.47 (s, 1H) 8.56 (s, 1H). MS [M+H]found 477.

Example: 52(S)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(2,2,2-trifluoroethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example: 53(R)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(2,2,2-trifluoroethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

The product of 51 (195 mg) was separated by chiral SFC (Chiralpak AD-Hcolumn, flowrate=1.25 mL/min, modifier 40% ethanol in liquid CO₂ to giveIsomer 1 (57.6 mg, t=1.21 min) and Isomer 2 (64.2 mg, t=2.07 min).

Example 541-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

To 2,4-dichloropyrimidin-5-amine (6.22 g, 38.0 mmol) in 16.5 mL ofdichloromethane was added dry tetrahydrofuran-3-carbaldehyde (3.8 g,38.0 mmol). The solution was cooled to 0° C. A solution of titaniumtetrachloride (41.8 ml, 41.8 mmol) in 10 mL of dichloromethane was addedslowly. The reaction mixture was stirred at for 2 hours. Sodiumtriacetoxyborohydride (24.13 g, 114 mmol) was added in 4 equal portionsover about 10 minutes and the mixture was stirred at room temperaturefor 48 hours. The reaction mixture was then diluted with water andextracted twice with methyl-t-butyl ether. The organic layers werecombined, dried over magnesium sulfate, filtered, and evaporated invacuo to give 8.2 g of2,4-dichloro-N-((tetrahydrofuran-3-yl)methyl)pyrimidin-5-amine as a tansolid which was used without further purification. [M+H] found 249.

2,4-Dichloro-N-((tetrahydrofuran-3-yl)methyl)pyrimidin-5-amine (7 g,28.2 mmol), morpholine-3-carboxylic acid hydrochloride (832 mg, 4.97mmol), and DIPEA (2.67 ml, 15.28 mmol) were combined in DMSO (8 ml). Thereaction mixture was heated overnight at 100° C. Upon cooling thesolution was diluted with water then extracted twice with ethyl acetate.The organic layers were combined, dried over magnesium sulfate,filtered, and evaporated in vacuo to give 6.6 g of2-chloro-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a brown oil which was used without further purification. [M+H] found325.

2-Chloro-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(320 mg, 0.985 mmol) and iodomethane (0.307 ml, 4.93 mmol) were frozenin DMSO (2 ml). Sodium 2-methylpropan-2-olate (284 mg, 2.96 mmol) wasadded and covered by a layer of DMSO. The mixture was allowed to warm toroom temperature and stir for 1 hour, then was diluted with water thenextracted twice with EtOAc. The organic layers were combined, dried overmagnesium sulfate, filtered, and evaporated in vacuo to give 390 mg of2-chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-oneas a tan oil. [M+H] found 339.

2-Chloro-6a-methyl-5-((tetrahydrofuran-3-yl)methyl)-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(390 mg, 1.151 mmol) PdCl₂(dppf)-CH₂Cl₂ (188 mg, 0.230 mmol),1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(417 mg, 1.381 mmol) and sodium 2-methylpropan-2-olate (1.5 ml, 1.151mmol) were combined in 1,4-dioxane (3 ml). The suspension was heated bymicrowave irradiation at 100° C. for 30 minutes, the reaction wasfiltered, cooled, and purified by mass-triggered preparative HPLC using22-25% ACN (containing 0.035% TFA) in water (containing 0.05% TFA) on aPhenomenex Gemini 5 μm C18, 75×30 mm column). Product containingfractions were evaporated in vacuo to give a residue. The residue wasdissolved in methanol for transfer. The solvent was removed under astream of nitrogen gas to give 85 mg of the title compound as a paleyellow solid. ¹H NMR (400 MHz, MeOD) δ ppm 0.48-0.57 (m, 2H) 0.71-0.79(m, 2H) 1.73 (s, 3H) 1.73 (m, 1H) 2.02-2.14 (m, 1H) 2.61 (m, 1H)2.68-2.80 (m, 1H) 3.55-3.65 (m, 2H) 3.68 (dd, J=12, 4 Hz, 1H) 3.71-3.81(m, 3H) 3.84 (d, J=12 Hz, 2H) 3.91-4.05 (m, 2H) 4.08-4.21 (m, 2H) 4.75(d, J=16 Hz, 1H) 7.67 (d, J=8 Hz, 2H) 8.03 (s, 1H) 8.11 (dd, J=8, 4 Hz,2H) [M+H] found 479.

Example 55(S,S)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaExample 56(S,R)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaExample 57(R,S)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaand Example 58(R,R)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

Cyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)ureaas prepared in Example 54 was chirally separated by HPLC (Chiralpak AD-Hcolumn, flowrate=50 mL/min, eluting with 35% methanol in DCM) to give:Isomer 1: ¹H NMR (400 MHz, MeOD) δ ppm 0.48-0.56 (m, 2H) 0.70-0.82 (m,2H) 1.45 (s, 3H) 1.75 (m, 1H) 1.96-2.13 (m, 1H) 2.60 (m, 1H) 2.68-2.81(m, 1H) 3.34 (s, 1H) 3.45-3.55 (m, 1H) 3.56-3.66 (m, 1H) 3.69-3.82 (m,3H) 3.88-4.02 (m, 2H) 4.02-4.18 (m, 3H) 4.28 (dd, J=12, 4 Hz, 1H) 7.48(d, J=8 Hz, 2H) 8.14-8.25 (m, 3H) Retention time: 3.57 min; Isomer 2: ¹HNMR (400 MHz, MeOD) δ ppm 0.44-0.56 (m, 2H) 0.67-0.79 (m, 2H) 1.45 (s,3H) 1.66-1.79 (m, 1H) 1.94-2.08 (m, 1H) 2.60 (m, 1H) 2.66-2.80 (m, 1H)3.35 (d, J=4 Hz, 1H) 3.50 (m, 1H) 3.57-3.65 (m, 1H) 3.65-3.88 (m, 3H)3.88-3.97 (m, 2H) 3.97-4.15 (m, 3H) 4.28 (dd, J=12, 4 Hz, 1H) 7.48 (d,J=8 Hz, 2H) 8.12-8.27 (m, 3H) Retention time: 5.13 min; Isomer 3: ¹H NMR(400 MHz, MeOD) δ ppm 0.47-0.56 (m, 2H) 0.70-0.79 (m, 2H) 1.45 (s, 3H)1.66-1.78 (m, 1H) 1.96-2.07 (m, 1H) 2.60 (m, 1H) 2.66-2.81 (m, 1H)3.33-3.37 (m, 1H) 3.57-3.71 (m, 2H) 3.71-3.82 (m, 3H) 3.93 (m, 1H)3.97-4.08 (m, 2H) 4.08-4.15 (m, 2H) 4.28 (dd, J=12, 4 Hz, 1H) 7.48 (d,J=8 Hz, 2H) 8.12-8.26 (m, 3H) Retention time: 8.13 min; and Isomer 4: ¹HNMR (400 MHz, MeOD) δ ppm 0.48-0.58 (m, 2H) 0.71-0.81 (m, 2H) 1.47 (s,3H) 1.67-1.82 (m, 1H) 1.99-2.13 (m, 1H) 2.60 (m, 1H) 2.71-2.82 (m, 1H)3.34-3.37 (m, 1H) 3.58-3.71 (m, 2H) 3.72-3.81 (m, 3H) 3.93-4.02 (m, 2H)4.03-4.16 (m, 3H) 4.28 (dd, J=12, 4 Hz, 1H) 7.49 (d, J=8 Hz, 2H)8.13-8.26 (m, 3H) Retention time: 12.45 min.

Preparation: 42-chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one

2,2-Difluoropropan-1-ol (383 mg, 3.99 mmol) was combined with THF (3mL). The solution was stirred at room temperature as4-nitrobenzene-1-sulfonyl chloride (931 mg, 4.20 mmol) was addedfollowed by triethylamine (0.611 mL, 4.39 mmol). After about 28 hours,the reaction mixture was diluted with THF (2 mL) and4-dimethylaminopyridine (23 mg, 0.188 mmol) was added. After 16 hoursthe reaction mixture was diluted with 12 mL MTBE and 5 mL water andstirred for 5 minutes before the layers were separated. The organiclayer was extracted with 1 M HCl (3 mL), 5% sodium carbonate (3 mL),brine (3 mL), and then water (3 mL). The organic layer was diluted withanother 10 mL MTBE and extracted three times with 1 M NaOH (5 mL) andthen water (5 mL). The organic layer was dried over sodium sulfate,filtered, concentrated on a rotovap, and dried under vacuum to give2,2-difluoropropyl 4-nitrobenzenesulfonate (526 mg) as a pale yellowsolid.

2-Chloro-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(384 mg, 1.508 mmol), 2,2-difluoropropyl 4-nitrobenzenesulfonate (767mg, 2.73 mmol), cesium carbonate (1240 mg, 3.81 mmol) were combined inDMA (2 mL) at ambient temperature for about 1 hour and then heated in anoil bath at 60° C. After about 22 hours, the reaction mixture wasallowed to cool to ambient temperature, diluted reaction mixture with 25mL EtOAc, transferred to a separatory funnel, and the reaction vesselrinsed twice with 10 mL 1:1 EtOAc/water. An additional 10 mL of waterwas then added, the layers were mixed and then separated. The organiclayer was extracted with water (10 mL) and the combined aqueous layerswere extracted with 10 mL of EtOAc, which was then extracted with 5 mLbrine. The combined organic layers were dried over sodium sulfate,filtered, and concentrated on a rotovap to give a residue. The residuewas combined with isopropanol (5 mL) and heated in an oil bath at 50° C.oil bath. An addition 1.5 mL was added and the solution was allowed tocool to ambient temperature with stirring to give a solid. Collected thesolid by filtration, rinse the filter cake with 1 mL isopropanol and airdry for 2 hours, then dry under vacuum to give the title compound.

Example: 591-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea

2-Chloro-5-(2,2-difluoropropyl)-6a-methyl-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-6(5H)-one(707 mg, 2.125 mmol) and1-cyclopropyl-3-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea(770 mg, 2.55 mmol) where combined in methyltetrahydrofuran (10 mL) andaqueous sodium carbonate (2 M) (2.2 mL). The reaction mixture was heatedin a 50° C. oil bath and then 1,1-bis(di-tert-butylphosphino)ferrocenepalladium dichloride (38 mg) was added. The reaction mixture was thenplaced in an 80° C. oil bath. After about 1 hour the oil bath wasreduced to 74° C. After about 4 hours some solvent had evaporated, 6 mLde-gassed methyltetrahydrofuran was added and decreased the oil bathtemperature to 70° C. After about 6 hours, solvent had again evaporated,6 mL de-gassed methyltetrahydrofuran was added. After another hour,1,1-bis(di-tert-butylphosphino)ferrocene palladium dichloride (9 mg) wasadded and heating continued at 70° C. for 3 hours, then cooled to roomtemperature and allowed to stir overnight. The reaction mixture was thendiluted with 4 mL 1:1 methyltetrahydrofuran/water, stir for 15 minutes,the solids were collected by filtration, the filter cake washed with 2×3mL portions of 1:5 water/methyltetrahydrofuran, air-dried for 1 hour,then under vacuum for 1 hour to give the title compound.

The compounds of the invention can be administered alone or in the formof a pharmaceutical composition. In practice, the compounds of theinvention are usually administered in the form of pharmaceuticalcompositions, that is, in admixture with pharmaceutically acceptableexcipients the proportion and nature of which are determined by theproperties of the selected compound of the invention, the chosen routeof administration, and standard pharmaceutical practice.

In another embodiment, the present invention provides pharmaceuticalcompositions comprising: a compound of invention and a pharmaceuticallyacceptable excipient.

In effecting treatment of a patient in need of such treatment, acompound of the invention can be administered in any form and routewhich makes the compound bioavailable. The compounds of the inventioncan be administered by a variety of routes, including oral andparenteral routes, more particularly by inhalation, subcutaneously,intramuscularly, intravenously, transdermally, intranasally, rectally,vaginally, occularly, topically, sublingually, and buccally,intraperitoneally, intravenously, intraarterially, transdermally,sublingually, intramuscularly, rectally, transbuccally, intranasally,intraadiposally, intrathecally and via local delivery for example bycatheter or stent.

One skilled in the art can readily select the proper form and route ofadministration depending upon the particular characteristics of thecompound selected, the disorder or condition to be treated, the stage ofthe disorder or condition, and other relevant circumstances. Thepharmaceutical compositions of the invention may be administered to thepatient, for example, in the form of tablets, capsules, cachets, papers,lozenges, wafers, elixirs, ointments, transdermal patches, aerosols,inhalants, suppositories, solutions, and suspensions.

The pharmaceutical compositions of the present invention are prepared ina manner well known in the pharmaceutical art and include at least oneof the compounds of the invention as the active ingredient. The amountof a compound of the present invention may be varied depending upon itsparticular form and may conveniently be between 1% to about 70% of theweight of the unit dosage form. The term “pharmaceutically acceptableexcipient” refers to those typically used in preparing pharmaceuticalcompositions and should be pharmaceutically pure and non-toxic in theamounts used. They generally are a solid, semi-solid, or liquid materialwhich can serve as a vehicle or medium for the active ingredient. Someexamples of pharmaceutically acceptable excipients are found inRemington's Pharmaceutical Sciences and the Handbook of PharmaceuticalExcipients and include diluents, vehicles, carriers, ointment bases,binders, disintegrates, lubricants, glidants, sweetening agents,flavoring agents, gel bases, sustained release matrices, stabilizingagents, preservatives, solvents, suspending agents, buffers,emulsifiers, dyes, propellants, coating agents, and others.

The present pharmaceutical compositions are preferably formulated in aunit dosage form, each dosage typically containing from about 0.5 mg toabout 200 mg of the compounds of the invention. The term “unit dosageform” refers to a physically discrete unit suitable as a single dosage,each unit containing a predetermined quantity of active ingredient, inassociation with a suitable pharmaceutical excipient, by which one ormore is used throughout the dosing regimen to produce the desiredtherapeutic effect.

In one particular variation, the composition is a pharmaceuticalcomposition adapted for oral administration, such as a liquidformulation, for example, a solution or suspension, adapted for oraladministration or a tablet or a capsule. In still another particularvariation, the pharmaceutical composition is a liquid formulationadapted for parenteral administration.

In another embodiment, the invention provides methods of treatingconditions associated with mTOR, comprising: administering to a patientin need thereof an effective amount of a compound of the invention. Inanother embodiment, the invention provides a method of inhibiting amTOR: comprising, contacting the enzyme with a compound of theinvention. In a further embodiment, the invention provides a method ofinhibiting a mTOR: comprising, administering a first compound to asubject that is converted in vivo to a compound of the invention.

In another embodiment, compounds of the invention, including thecompound of formula I, are provided for use as a medicament. Theinvention also provides the use of compounds of the invention, includingthe use for the manufacture of a medicament, to treat the conditionsassociated with mTOR described herein. The compounds of the presentinvention are stable and are relatively safe in their end use. Thecompounds of the present invention are useful as mTOR inhibitors for avariety of subjects (e.g., humans, non-human mammals and non-mammals).

As used herein terms “condition,” “disorder,” and “disease” relate toany unhealthy or abnormal state. The term “conditions associated withmTOR” includes disorders and diseases in which the inhibition of mTORprovides a therapeutic benefit, such as cancer, allergy/asthma, diseasesand conditions of the immune system, inflammation, disease andconditions of the central nervous system (CNS), cardiovascular disease,viral infections, dermatological disease, and diseases and conditionsrelated to uncontrolled angiogenesis, and the like. Where general termsare used herein to describe conditions associated with mTOR it isunderstood that the more specifically described conditions mentioned inthe various diagnostic manuals and other materials are included withinthe scope of this invention.

For example, it is understood that the treatment of cancer includestreatment of all neoplasia, regardless of their histopathologicalappearance. Particularly, the cancers that can be treated include, butare not limited to, cancer of blood, including leukemia (including acutemyelogenous leukemia, chronic myelogenous leukemia, acute lymphocyticleukemia, chronic lymphocytic leukemia), cancer of the skin, includingmelanoma, basal cell carcinoma, and squamous cell carcinoma, bone,liver, lung (including small-cell lung tumor, non small-cell lung cancerand bronchioalveolar cancer), brain, breast, prostate, larynx, gallbladder, pancreas, rectum, bile duct, parathyroid, thyroid, adrenal,neural tissue, bladder, spleen, head and neck, included the jaw, mouth,and nose, colon, stomach, testes, esophagus, uterus, cervix and vulva,colorectal, bronchi, bile duct, bladder, kidney, ovary, pancreas,multiple myeloma, lymphomas, basal cell carcinoma, squamous cellcarcinoma of both ulcerating and papillary type, osteo sarcoma, Ewing'ssarcoma, veticulum cell sarcoma, myeloma, giant cell tumor, islet celltumor, acute and chronic lymphocytic and granulocytic tumors, hairy-celltumor, adenoma, hyperplasia, medullary carcinoma, pheochromocytoma,mucosal neuronms, intestinal ganglioneuromas, hyperplastic corneal nervetumor, marfanoid habitus tumor, Wilm's tumor, seminoma, ovarian tumor,leiomyomater tumor, cervical dysplasia and in situ carcinoma,neuroblastoma, retinoblastoma, myelodysplastic syndrome, mycosisfungicide, rhabdomyosarcoma, astrocytoma, non-Hodgkin's lymphoma,Kaposi's sarcoma, osteogenic and other sarcoma, malignant hypercalcemia,polycythermia vera, adenocarcinoma, glioblastoma multiforma, glioma,lymphomas, epidermoid carcinomas, and other carcinomas and sarcomas.

Benign tumors may also be treated by the mTOR inhibitors of the presentinvention and include, but are not limited to, hemangiomas,hepatocellular adenoma, cavernous haemangioma, focal nodularhyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bileduct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas,myxomas, nodular regenerative hyperplasia, trachomas, pyogenicgranulomas, and the like, and hamartoma conditions such as Peutz-JeghersSyndrome (PJS), Cowden disease, Bannayan-Riley-Ruvalcaba Syndrome(BRRS), Proteus syndrome, Lhermitte-Duclos disease and TuberousSclerosis (TSC).

The mTOR inhibitors of the present invention may also be used to treatabnormal cell proliferation due to insults to body tissue duringsurgery. These insults may arise as a result of a variety of surgicalprocedures such as joint surgery, bowel surgery, and cheloid scarring.Diseases that produce fibrotic tissue include emphysema. Repetitivemotion disorders that may be treated using the present invention includecarpal tunnel syndrome.

The mTOR inhibitors of the invention may also be useful in theprevention of restenosis, that is the control of undesired proliferationof normal cells in the vasculature in response to the introduction ofstents in the treatment of vasculature disease.

Proliferative responses associated with organ transplantation that maybe treated using mTOR inhibitors of the invention include proliferativeresponses contributing to potential organ rejections or associatedcomplications. Specifically, these proliferative responses may occurduring transplantation of the heart, lung, liver, kidney, and other bodyorgans or organ systems.

The mTOR inhibitors of the invention may also be useful the treatment ofabnormal angiogenesis including the abnormal angiogenesis accompanyingrheumatoid arthritis, ischemic-reperfusion related brain edema andinjury, cortical ischemia, ovarian hyperplasia and hypervascularity,(polycystic ovary syndrome), endometriosis, psoriasis, diabeticretinopaphy, and other ocular angiogenic diseases such as retinopathy ofprematurity (retrolental fibroplastic), macular degeneration, cornealgraft rejection, neuroscular glaucoma, Oster Webber syndrome,retinal/choroidal neuvascularization and corneal neovascularization,Best's disease, myopia, optic pits, Stargart's diseases, Pagets disease,vein occlusion, artery occlusion, sickle cell anemia, sarcoid, syphilis,pseudoxanthoma elasticum carotid abstructive diseases, chronicuveitis/vitritis, mycobacterial infections, Lyme's disease, systemiclupus erythematosis, retinopathy of prematurity, Eales disease, diabeticretinopathy, macular degeneration, Bechets diseases, infections causinga retinitis or chroiditis, presumed ocular histoplasmosis, parsplanitis, chronic retinal detachment, hyperviscosity syndromes,toxoplasmosis, trauma and post-laser complications, diseases associatedwith rubesis (neovascularization of the angle), diseases caused by theabnormal proliferation of fibrovascular or fibrous tissue including allforms of proliferative vitreoretinopathy, atopic keratitis, superiorlimbic keratitis, pterygium keratitis sicca, sjogrens, acne rosacea,phylectenulosis, diabetic retinopathy, retinopathy of prematurity,corneal graft rejection, Mooren's ulcer, Terrien's marginaldegeneration, marginal keratolysis, polyarteritis, Wegener sarcoidosis,scleritis, periphigoid radial keratotomy, neovascular glaucoma andretrolental fibroplasia, syphilis, Mycobacteria infections, lipiddegeneration, chemical burns, bacterial ulcers, fungal ulcers, Herpessimplex infections, Herpes zoster infections, protozoan infections, andKaposi sarcoma, Alzheimer's disease, Parkinson's disease amyotrophiclateral sclerosis (ALS), epilepsy, seizures, Huntington's disease,polyglutamine diseases, traumatic brain injury, ischemic andhemorrhaging stroke, cerebral ischemias or neurodegenerative disease,including apoptosis-driven neurodegenerative disease, caused bytraumatic injury, acute hypoxia, ischemia or glutamate neurotoxicity.

For example, it is understood that the treatment of inflammationinclude, but are not limited to, acute pancreatitis, chronicpancreatitis, asthma, allergies, chronic obstructive pulmonary disease,adult respiratory distress syndrome. and chronic inflammatory diseasesassociated with uncontrolled angiogenesis, inflammatory bowel diseasessuch as Crohn's disease and ulcerative colitis, psoriasis, sarcoidois,and rheumatoid arthritis, sarcoidosis, and multisystem granulomatousdisorder.

For example, it is understood that the treatment of autoimmune includes,but are not limited to, glomerulonephritis, rheumatoid arthritis,systemic lupus erythematosus, scleroderma, chronic thyroiditis, Graves'disease, autoimmune gastritis, diabetes, autoimmune hemolytic anemia,autoimmune neutropenia, thrombocytopenia, atopic dermatitis, chronicactive hepatitis, myasthenia gravis, multiple sclerosis, inflammatorybowel disease, ulcerative colitis, Crohn's disease, psoriasis, graft vs.host disease, multiple sclerosis, or Sjoegren's syndrome.

The mTOR inhibitors of the present invention are also useful fortreating obesity, diabetes, insulin resistance, metabolic syndrome, andhyperlipidemia.

A wide variety of therapeutic agents may have a therapeutic additive orsynergistic effect with mTOR inhibitors according to the presentinvention. Combination therapies that comprise one or more compounds ofthe present invention with one or more other therapeutic agents can beused, for example, to: 1) enhance the therapeutic effect(s) of the oneor more compounds of the present invention and/or the one or more othertherapeutic agents; 2) reduce the side effects exhibited by the one ormore compounds of the present invention and/or the one or more othertherapeutic agents; and/or 3) reduce the effective dose of the one ormore compounds of the present invention and/or the one or more othertherapeutic agents. It is noted that combination therapy is intended tocover when agents are administered before or after each other(sequential therapy) as well as when the agents are administered at thesame time.

Examples of such therapeutic agents that may be used in combination withthe present mTOR inhibitors include, but are not limited to, anti-cellproliferation agents, anticancer agents, alkylating agents, antibioticagents, antimetabolic agents, hormonal agents, plant-derived agents, andbiologic agents.

Examples of such therapeutic agents that may be used in combination withmTOR inhibitors include, but are not limited to, anti-cell proliferationagents, anticancer agents, alkylating agents, antibiotic agents,antimetabolic agents, hormonal agents, plant-derived agents, andbiologic agents.

Anti-cell proliferation agents useful in combination with the mTORinhibitors of the present invention include, but are not limited to,retinoid acid and derivatives thereof, 2-methoxyestradiol, ANGIOSTATIN™protein, ENDOSTATIN™ protein, suramin, squalamine, tissue inhibitor ofmetalloproteinase-I, tissue inhibitor of metalloproteinase-2,plasminogen activator inhibitor-1, plasminogen activator inhibitor-2,cartilage-derived inhibitor, paclitaxel, platelet factor 4, protaminesulphate (clupeine), sulphated chitin derivatives (prepared from queencrab shells), sulphated polysaccharide peptidoglycan complex (sp-pg),staurosporine, modulators of matrix metabolism, including for example,proline analogs ((1-azetidine-2-carboxylic acid (LACA),cishydroxyproline, d,l-3,4-dehydroproline, thiaproline,beta-aminopropionitrile fumarate,4-propyl-5-(4-pyridinyl)-2(3H)-oxazolone, methotrexate, mitoxantrone,heparin, interferons, 2 macroglobulin-serum, chimp-3, chymostatin,beta-cyclodextrin tetradecasulfate, eponemycin; fumagillin, gold sodiumthiomalate, d-penicillamine (CDPT), beta-1-anticollagenase-serum,alpha-2-antiplasmin, bisantrene, lobenzarit disodium,n-(2-carboxyphenyl-4-chloroanthronilic acid disodium or “CCA”,thalidomide, angostatic steroid, carboxynaminolmidazole,metalloproteinase inhibitors such as BB94. Other anti-angiogenesisagents that may be used include antibodies, preferably monoclonalantibodies against these angiogenic growth factors: bFGF, aFGF, FGF-5,VEGF isoforms, VEGF-C, HGF/SF and Ang-1/Ang-2.

Inhibitors of MEK, MAPK, or ERK kinases are useful in combination withthe compounds of the present invention. Specifically,(R)-3-(2,3-Dihydroxypropyl)-6-fluoro-5-(2-fluoro-4-iodophenylamino)-8-methylpyrido[2,3-d]pyrimidine-4,7(3H,8H)-dioneuseful in combination with the compounds of the present invention.Inhibitors of Hedgehog kinase are useful in combination with thecompounds of the present invention. Proteasome inhibitors, in particularbortezomib is useful in combination with the compounds of the presentinvention.

Alkylating agents useful in combination with the present mTOR inhibitorsinclude, but are not limited to, bischloroethylamines (nitrogenmustards, e.g. chlorambucil, cyclophosphamide, ifosfamide,mechlorethamine, melphalan, uracil mustard), aziridines (e.g. thiotepa),alkyl alkone sulfonates (e.g. busulfan), nitrosoureas (e.g. carmustine,lomustine, streptozocin), nonclassic alkylating agents (altretamine,dacarbazine, and procarbazine), platinum compounds (carboplastin andcisplatin). Combination therapy including a mTOR inhibitor and analkylating agent is expected to have therapeutic synergistic effects inthe treatment of cancer and reduce sides affects associated with thesechemotherapeutic agents.

Examples of antibiotic agents useful in combination with the presentmTOR inhibitors include, but are not limited to, anthracyclines (e.g.doxorubicin, daunorubicin, epirubicin, idarubicin and anthracenedione),mitomycin C, bleomycin, dactinomycin, plicatomycin. These antibioticagents interfere with cell growth by targeting different cellularcomponents.

Antimetabolic agents useful in combination with the present mTORinhibitors include, but are not limited to, fluorouracil (5-FU),floxuridine (5-FUdR), methotrexate, leucovorin, hydroxyurea, thioguanine(6-TG), mercaptopurine (6-MP), cytarabine, pentostatin, fludarabinephosphate, cladribine (2-CDA), asparaginase, and gemcitabine.Combination therapy including a mTOR inhibitor and an antimetabolicagent is expected to have therapeutic synergistic effects on cancer andreduce sides affects associated with these chemotherapeutic agents.

Hormonal agents useful in combination with the present mTOR inhibitorsinclude synthetic estrogens (e.g. diethylstibestrol), antiestrogens(e.g. tamoxifen, toremifene, fluoxymesterol and raloxifene),antiandrogens (bicalutamide, nilutamide, and flutamide), aromataseinhibitors (e.g., aminoglutethimide, anastrozole and tetrazole),ketoconazole, goserelin acetate, leuprolide, megestrol acetate andmifepristone. Combination therapy including a mTOR inhibitor and ahormonal agent is expected to have therapeutic synergistic effects oncancer and reduce sides affects associated with these chemotherapeuticagents.

Plant-derived agents useful in combination with the present mTORinhibitors include, but are not limited to, vinca alkaloids (e.g.,vincristine, vinblastine, vindesine, vinzolidine and vinorelbine),podophyllotoxins (e.g., etoposide (VP-16) and teniposide (VM-26)),taxanes (e.g., paclitaxel and docetaxel). These plant-derived agentsgenerally act as antimitotic agents that bind to tubulin and inhibitmitosis. Podophyllotoxins such as etoposide are believed to interferewith DNA synthesis by interacting with topoisomerase II, leading to DNAstrand scission. Combination therapy including an mTOR inhibitor and aplant-derived agent is expected to have therapeutic synergistic effectson cancer and reduce sides affects associated with thesechemotherapeutic agents

The terms “treat,” “treatment,” and “treating” include improvement ofthe conditions described herein. Also, it is also recognized that oneskilled in the art may affect the conditions by treating a patientpresently afflicted with the disorders or by prophylactically treating apatient believed to be susceptible to such conditions with an effectiveamount of a compound of invention. Thus, the terms “treat,” “treatment,”and “treating” include all processes providing slowing, interrupting,arresting, controlling, or stopping of the state or progression of theconditions described herein, but does not necessarily indicate a totalelimination of all symptoms or a cure of the condition, and is intendedto include prophylactic and therapeutic treatment of such disorders.

As used herein the terms “patient” and “subject” includes humans andnon-human animals, for example, mammals, such as mice, rats, guineapigs, dogs, cats, rabbits, cows, horses, sheep, goats, and pigs. Theterm also includes birds, fish, reptiles, amphibians, and the like. Itis understood that a more particular patient is a human. Also, moreparticular patients and subjects are non-human mammals, such as mice,rats, and dogs.

As used herein, the term “effective amount” refers to the amount ofcompound of the invention which treats, upon single or multiple doseadministration, a patient suffering from the mentioned condition. Aneffective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount, the dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of patient; its size, age, and general health; thespecific condition, disorder, or disease involved; the degree of orinvolvement or the severity of the condition, disorder, or disease, theresponse of the individual patient; the particular compoundadministered; the mode of administration; the bioavailabilitycharacteristics of the preparation administered; the dose regimenselected; the use of concomitant medication; and other relevantcircumstances. An effective amount of the present use invention,including a compound of the invention, is expected to vary from about0.1 milligram per kilogram of body weight per day (mg/kg/day) to about40 mg/kg/day. Specific amounts can be determined by the skilled person.

In a particular embodiment the present invention provides a method fortreating cancer, comprising: administering to a patient in need thereofan effective amount of a compound of invention.

The invention also provides an article of manufacture: comprising atleast one compound of the invention and a label. The label may includeinformation about the manufacturer, doses, conditions to be treated, andthe use of the compound or pharmaceutical composition.

In another embodiment the invention provides a kit: comprising, at leastone compound of the invention, a label, and apparatus foradministration. The apparatus may include mixing vials, liquids forforming solutions or suspensions, tubing, syringes, and the like.

The activity of compounds as mTOR inhibitors may be determined by avariety of methods, including in vitro and in vivo methods.

Example A Inhibition of mTOR

Purified mTOR are purchased from Invitrogen. mTOR activity wasdetermined using Invitrogen's LanthaScreen system. The inhibitoryproperties of compounds relative to mTOR may be determined using a black384-well-plate format in the following buffer 50 mM Hepes, 10 mM NaCl,10 mM MgCl₂, 0.2 mM EDTA, 0.01% Brij35, 2 mM DTT at pH7.3. The testcompound is prepared in DMSO using 2 fold serial dilutions for 11 datapoints which are added to the buffer so that each dilution contains 3%DMSO.

An Assay for mTOR Inhibition is as Follows:

Combine in each well 2 μl of 1.2 μM GFP-4E-BP1 (Invitrogen) and 150 μMATP (in buffer), 2 μl of diluted test compound (3% DMSO in buffer), and2 μl of 6 nM mTor in buffer. The reaction mixture is then incubated atroom temperature for 30 min, and quenched by adding 40 mM ETDA with 4 nMTb-anti-p4E-BP1 [pThr46] antibody in TR-FRET dilution buffer(Invitrogen). The plate is kept at room temperature for 1 hour and thenread using PheraStar (BMG labtech) LanthaScreen mode.

pIC₅₀ values, the negative of the log of the IC₅₀, are calculated bynon-linear curve fitting of the compound concentrations and percent ofinhibition to the standard pIC₅₀ equation. The exemplified compoundsinhibited human mTOR in the assay of Example A with a pIC₅₀ of: A lessthan about 6, B between 6 and 7.5, and C greater than 7.5 as indicatedin Table 1.

TABLE 1 Example pIC₅₀ Example pIC₅₀ Example pIC₅₀ 1 C 3 C 4 B 5 C 6 B 7C 9 C 11 B 14 B 15 C 16 C 17 B 18 C 19 B 20 A 22 B 23 B 24 A 26 C 28 C30 C 35 C 36 C 41 C 45 B 46 C 47 C 49 C 53 C

What is claimed is:
 1. A compound of the formula

G₁ is selected from the group consisting of N and CR₇; G₂ is selectedfrom the group consisting of C═O and CH₂; Ar is selected from the groupconsisting of C₄₋₁₄ aryl and C₁₋₁₀ heteroaryl; m is 0, 1, 2, 3, or 4; R₁is, each time taken, independently selected from the group consisting ofhalo, cyano, optionally substituted C₁₋₆ alkyl, C₁₋₈ sulfonyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₁₋₄ alkoxy, C₀₋₈ alkylamino, optionallysubstituted C₄₋₁₄ aryl, optionally substituted C₄₋₁₄ aryloxy, optionallysubstituted C₁₋₁₀ heteroaryloxy, C₁₋₅ oxycarbonyl, C₁₋₅ carbonyloxy,optionally substituted C₃₋₈ cycloalkyl, optionally substituted C₃₋₆heterocycloalkyl, optionally substituted C₁₋₁₀ heteroaryl, hydroxy,nitro, —C(O)NR₈R₉, —NHC(O)NR₈R₉, —NHC(O)OR₁₀, —NH(SO₂)NHR₈,—NHC(O)NHNR₈R₉, —NHC(S)NR₈R₉, —NHC(═NR₁₁)NR₈R₉, —NHC(SR₁₂)NR₈R₉, and—NHC(═NR₁₁)OR₁₃; R₂ is selected from the group consisting of hydrogen,halo, cyano, optionally substituted C₁₋₆ alkyl, C₁₋₈ sulfonyl,optionally substituted C₂₋₄ alkenyl, optionally substituted C₂₋₄alkynyl, optionally substituted C₁₋₄ alkoxy, C₀₋₈ alkylamino, optionallysubstituted C₄₋₁₄ aryl, optionally substituted C₄₋₁₄ aryloxy, C₁₋₅oxycarbonyl, C₁₋₅ carbonyloxy, optionally substituted C₃₋₆heterocycloalkyl, optionally substituted C₁₋₁₀ heteroaryl, hydroxy, andnitro; R₃ is selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl, andoptionally substituted C₃₋₆ heterocycloalkyl; R₄ is selected from thegroup consisting of methyl and trifluoromethyl; R₅ is selected from thegroup consisting of hydrogen, halo, optionally substituted C₁₋₆ alkyl,optionally substituted C₂₋₄ alkenyl, and optionally substituted C₃₋₈cycloalkyl; R₆ is selected from the group consisting of hydrogen, halo,optionally substituted C₁₋₆ alkyl, optionally substituted C₂₋₄ alkenyl,and optionally substituted C₃₋₈ cycloalkyl; or R₅ and R₆ are takentogether to form an optionally substituted C₁-C₃ alkylenyl; or R₄ and R₅are taken together to form an optionally substituted C₁-C₃ alkylenyl; orR₄ and R₆ are taken together to form an optionally substituted C₁-C₃alkylenyl; and R₇ is selected from the group consisting of hydrogen,C₀₋₈ alkylamino, C₁₋₇ amido, C₁₋₉ amide, C₁₋₅ carbamoyl, C₁₋₆sulfonylamido, C₀₋₆ sulfonylamino, C₁₋₅ ureido, optionally substitutedC₁₋₄ alkyl, optionally substituted C₁₋₄ alkoxy, cyano, halo, hydroxyl,nitro, C₁₋₅ oxycarbonyl, and C₁₋₈ sulfonyl; R₈ is, each time taken,independently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₃₋₈ cycloalkyl,optionally substituted C₄₋₁₄ aryl, optionally substituted C₃₋₆heterocycloalkyl, and optionally substituted C₁₋₁₀ heteroaryl; R₉ is,each time taken, independently selected from the group consisting ofhydrogen, optionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₄₋₁₄ aryl, optionally substitutedC₃₋₆ heterocycloalkyl, and optionally substituted C₁₋₁₀ heteroaryl; R₁₀is, each time taken, independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈cycloalkyl, optionally substituted C₄₋₁₄ aryl, and optionallysubstituted C₃₋₆ heterocycloalkyl; R₁₁ is, each time taken,independently selected from the group consisting of hydrogen, optionallysubstituted C₁₋₆ alkyl, optionally substituted C₁₋₆ alkoxy, optionallysubstituted C₃₋₈ cycloalkyl, optionally substituted C₄₋₁₄ aryl,optionally substituted C₃₋₆ heterocycloalkyl, optionally substitutedC₁₋₁₀ heteroaryl, cyano, and nitro; R₁₂ is, each time taken,independently selected from the group consisting of optionallysubstituted C₁₋₆ alkyl and optionally substituted phenyl; and R₁₃ is,each time taken, independently selected from the group consisting ofoptionally substituted C₁₋₆ alkyl, optionally substituted C₃₋₈cycloalkyl, and optionally substituted C₄₋₁₄ aryl; or thepharmaceutically acceptable salts thereof.
 2. A compound of claim 1wherein G₁ is N.
 3. A compound of claim 2 wherein G₂ is C═O.
 4. Acompound of claim 3 wherein Ar is C₄₋₁₄ aryl.
 5. A compound of claim 4wherein R₄ is methyl.
 6. A compound of claim 5 wherein R₃ is selectedfrom the group consisting of optionally substituted C₁₋₆ alkyl,optionally substituted C₃₋₆ heterocycloalkyl, and optionally substitutedC₃₋₈ cycloalkyl.
 7. A compound of claim 6 wherein R₃ is selected fromthe group consisting of C₁₋₄ alkyl, C₃₋₈ cycloalkylC₁₋₄ alkyl, and C₃₋₈cycloalkyl.
 8. A compound of claim 7 wherein R₅ is hydrogen and R₆ ishydrogen.
 9. A compound of claim 8 wherein m is at least 1 and at leastone of R₁ is selected from the group consisting of —NHC(O)NR₈R₉,—NHC(O)OR₁₀, and —NH(SO₂)NHR₈.
 10. A compound of claim 9 wherein m is atleast 1 and at least one of R₁ is selected from the group consisting of—NHC(O)NR₈R₉ and R₈ is hydrogen and R₉ is selected from the groupconsisting of C₁₋₄ alkyl, C₃₋₈ cycloalkylC₁₋₄ alkyl, and C₃₋₈cycloalkyl.
 11. A compound of claim 10 wherein R₂ is hydrogen.
 12. Acompound of claim 1 selected from the group consisting of1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylurea;1-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(S)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylurea;(R)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylurea;(S)-1-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-ethylurea;(S)-1-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(R)-1-cyclopropyl-3-(4-(5-(cyclopropylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-(4-(5-isobutyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-methyl-3-(4-(6a-methyl-5-((1-methyl-1H-pyrazol-3-yl)methyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-(4-(5-(3-hydroxy-2-(hydroxymethyl)-2-methylpropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5,6a-dimethyl-4-morpholino-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-isopropyl-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-(cyclobutylmethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-cyclopropyl-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-((6aS,7S)-5-(cyclopropylmethyl)-6a,7-dimethyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-46aR,9R)-5-(cyclopropylmethyl)-6a,9-dimethyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;ethyl2-methyl-2-(6a-methyl-2-(4-(3-methylureido)phenyl)-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)propanoate;2-methyl-2-(6a-methyl-2-(4-(3-methylureido)phenyl)-6-oxo-6a,7,9,10-tetrahydro-[1,4]oxazino[3,4-h]pteridin-5(6H)-yl)propanoicacid;1-(4-(5-(((S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-((S)-2,3-dihydroxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-((S)-5-(S)-2,3-dihydroxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-((R)-5-(S)-2,3-dihydroxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(S)-1-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(R)-1-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-methyl-3-(4-(6a-methyl-5-neopentyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-methyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydrofuran-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydrofuran-3-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-ethyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(S)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(R)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(tetrahydro-2H-pyran-4-yl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-(4-[5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea;(S)-1-(4-[5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea;(R)-1-(4-[5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea;1-(4-[5-(2-methoxyethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)-3-methylurea;1-ethyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-cyclopropyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(S)-1-cyclopropyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(R)-1-cyclopropyl-3-(4-(5-(3-methoxypropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-(4-(5-(2-ethoxyethyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-(4-(5-(2-hydroxy-2-methylpropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)-3-methylurea;1-cyclopropyl-3-(4-[5-(1,1-dioxidotetrahydro-2H-thiopyran-4-yl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl]phenyl)urea;1-cyclopropyl-3-(4-(6a-methyl-5-(3-(methylsulfonyl)propyl)-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(S)-1-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(R)-1-cyclopropyl-3-(4-(5-(2,2-difluoropropyl)-6a-methyl-6-oxo-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(2,2,2-trifluoroethyl)-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(S)-1-cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(2,2,2trifluoroethyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;(R)cyclopropyl-3-(4-(6a-methyl-6-oxo-5-(2,2,2-trifluoroethyl)-5,6,6a,7,9,10-hexahydro[1,4]oxazino[3,4-h]pteridin-2-yl)phenyl)urea;andcyclopropyl-3-(4-(6a-methyl-6-oxo-5-((tetrahydrofuran-3-yl)methyl)-5,6,6a,7,9,10-hexahydro-[1,4]oxazino[3,4-h]pteridineyl)phenyl)urea; or a stereoisomer of any of the aforementionedcompounds; or a pharmaceutically acceptable salt of any of theaforementioned compounds.
 13. A pharmaceutical composition, comprising:a compound of claim 1 and a pharmaceutically acceptable excipient.
 14. Amethod of treating cancer comprising: administering to a patient in needthereof and effective amount of a compound of any one of claims 1 to 12.